Low-Temperature Photothermal Therapy: Strategies and Applications

Low-Temperature Photothermal Therapy: Strategies and Applications

PDF

Xiulin Yi, Qiu-Yi Duan, Fu-Gen Wu

Research. Vol 2021 Article ID 9816594

Less

Research. Vol 2021 Article ID 9816594

• Review Article •

Low-Temperature Photothermal Therapy: Strategies and Applications

Full

Xiulin Yi, Qiu-Yi Duan, Fu-Gen Wu

Affiliations

State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing 210096, China

Published: 2021-05-20 doi: 10.34133/2021/9816594

Outline

Abstract

Less

Although photothermal therapy (PTT) with the assistance of nanotechnology has been considered as an indispensable strategy in the biomedical field, it still encounters some severe problems that need to be solved. Excessive heat can induce treated cells to develop thermal resistance, and thus, the efficacy of PTT may be dramatically decreased. In the meantime, the uncontrollable diffusion of heat can pose a threat to the surrounding healthy tissues. Recently, low-temperature PTT (also known as mild PTT or mild-temperature PTT) has demonstrated its remarkable capacity of conquering these obstacles and has shown excellent performance in bacterial elimination, wound healing, and cancer treatments. Herein, we summarize the recently proposed strategies for achieving low-temperature PTT based on nanomaterials and introduce the synthesis, characteristics, and applications of these nanoplatforms. Additionally, the combination of PTT and other therapeutic modalities for defeating cancers and the synergistic cancer therapeutic effect of the combined treatments are discussed. Finally, the current limitations and future directions are proposed for inspiring more researchers to make contributions to promoting low-temperature PTT toward more successful preclinical and clinical disease treatments.

Cite this Article

Xiulin Yi, Qiu-Yi Duan, Fu-Gen Wu. Low-Temperature Photothermal Therapy: Strategies and Applications[J]. Research, 2021 , 2021 (5) : 9816594 - . DOI: 10.34133/2021/9816594

Full Text

Less

1. Introduction

Less

In the past few decades, photothermal therapy (PTT) which usually utilizes photothermal agents (PTAs) capable of generating abundant heat under light irradiation has been frequently applied to kill/inactivate tumors [1] or bacteria [2], and is thus acknowledged as one of the primary treatment strategies in clinical and preclinical phases. With the rapid development of nanotechnology, various nanomaterials have been constructed for a broad range of biomedical applications and have exhibited excellent performance in treating a variety of diseases, including bacterial infection [3], cancer [4], neural diseases [5], and cardiovascular diseases [6]. Compared to traditional thermal therapy methods, the nanomaterial-mediated hyperthermia can realize bacterium- or tumor-specific location by designing passive and/or active targeting nanoplatforms and achieve on-demand treatments via controlling the external energy sources like light. Under the external energy sources, the nanomaterials located at the targeted tissues can produce heat and the inside-out heating direction remarkably decreases undesirable damage to normal tissues, and moreover, the nanomaterial-mediated hyperthermia therapy holds great promise for spatiotemporally controllable disease treatments [1, 2, 7]. Additionally, especially for cancer treatments, PTT based on nanotechnology has been combined with other therapeutic modalities including chemotherapy, radiotherapy (RT), photodynamic therapy (PDT), gene therapy, immunotherapy, and chemodynamic therapy (CDT) to achieve synergistic treatments [8–10], which has been considered as a robust strategy for improving therapeutic efficacies. In the past decades, researchers have found a large number of nanomaterials possessing photothermal conversion capacity, which can be categorized into two groups—inorganic PTAs and organic PTAs. The inorganic PTAs include metal or metal-containing nanomaterials including gold nanostructures [11, 12], palladium-based nanostructures [13–15], iron or copper-containing nanoparticles (NPs) [16–19], transition metal chalcogenides [20], and quantum dots [21, 22]. On the other hand, organic materials [23] including near-infrared (NIR) dyes represented by cyanine dyes [24–32], conjugated polymers (e.g., polydopamine (PDA), polyaniline, polypyrrole, and poly(3,4-ethylenedioxythiophene)) [33–36], and some carbon-based nanomaterials (most of them are organic materials; as represented by graphite-related nanostructures) [37–41] have also been utilized for PTT.

There are several properties that dictate the satisfactory PTT efficacy of PTAs: (1) strong absorbance in the NIR region and superb photothermal conversion capacity, (2) acceptable biocompatibility and biosafety, and (3) the accessibility of surface modification for realizing quality improvement and multifunctionality. For (3), in terms of conquering bacterial infections, factors like the balance between hydrophobicity and cationic charges of nanomaterials should be considered; as for cancer treatments, factors including prolonged circulation time, low retention in liver and kidney, and pronounced tumor-accumulating/targeting ability for precise therapy need to be emphasized. Compared with other conventional therapeutic approaches, PTT possesses the typical advantages in terms of noninvasiveness, negligible toxicity to normal cells in the dark, and spatiotemporally controlled administration. Besides, through the employment of NIR light irradiation, much deeper tissue penetration for treating interior or deep-seated tumors, bacterial infections, or wounds can be achieved.

However, excessive hyperthermia poses an unavoidable threat to surrounding healthy tissues and may induce undesirable inflammation because of the difficulty in blocking heat diffusion. Moreover, in cancer treatments, there are some undesirable biological effects induced by high-temperature thermal ablation. On the one hand, since PTT that takes effect at a temperature above 50°C compels cells to death mainly through necrosis [7], which is supposed to cause the release of cellular fragments and intracellular biomolecules, violent local inflammation may appear resulting in the further damage to normal tissues and the increase in tumor metastasis [42]. On the other hand, it is considered that overheating at such high temperatures has the risk of impairing the immune antigens capable of evoking antitumor immunity and immune cells exceuting immune responses in the tumor microenvironment (TME), thus preventing immune system from conquering cancers [43, 44]. Further, to reach a temperature high enough to thoroughly kill cancer cells or bacteria requires high-quality NIR lasers and/or high-performance PTAs, which may increase the cost/consumption and then restrain the application in clinic.

For surmounting these bottlenecks, low-temperature PTT (also termed mild-temperature PTT or mild PTT) which preferentially eliminates bacteria or tumors and promotes wound healing under low temperatures with inconsiderable damage to normal tissues and inflammation has been proposed. A large number of studies have elucidated that low-temperature PTT can achieve fantastic therapeutic performance to enable practical biomedical applications. Although there are different temperature thresholds of low-temperature PTT, it is widely recognized that most of the mild hyperthermia treatments are conducted at temperatures below 48°C [7, 45]. Meanwhile, low-temperature PTT can be achieved under mild NIR laser irradiation with a laser density not higher than the permitted value 0.329 W/cm² (for 808 nm) for skin exposure [46]. Although it has been widely considered that the efficacy of mild hyperthermia can be dramatically compromised due to the elevated expression of heat shock proteins (HSPs) able to repair the heat injury and protect cells from apoptosis through multiple stress-related pathways, which leads to tumor thermal resistance [45, 47], there have been various strategies proven to be capable of solving this problem. Importantly, a large number of studies have demonstrated that mild heat can render the cancer cells and bacteria more vulnerable to other treatment modalities, thus elevating the effectiveness of other treatments [44, 45]. For example, hyperthermic perfusion chemotherapy (including hyperthermic isolated limb perfusion and hyperthermic intraperitoneal chemotherapy) systems have been utilized for cancer treatments in clinic for many years and exhibited satisfactory therapeutic effects [48, 49]. Furthermore, similar to conventional PTT, the rapid development of nanotechnology enables the use of various nanomaterials for achieving low-temperature PTT.

In this review, we comprehensively summarize and comment on the recent advances regarding the development of strategies for realizing low-temperature PTT and the utilization of low-temperature PTT for combating tumors and bacterial infections and facilitating wound healing (Figure 1). It is believed that the summarization of the low-temperature PTT strategies will inspire more researchers to adopt such an efficacious treatment modality to treat a variety of diseases (beyond bacterial infections, wounds, and cancers). Regarding the applications of low-temperature PTT, we will divide this part into three sections: (1) low-temperature PTT for treating bacterial infections, (2) low-temperature PTT for promoting wound healing, and (3) low-temperature PTT for cancer treatments. For the first and second parts, we will introduce the preparation and composition of the reported platforms and discuss the effectiveness of mild PTT in antibiosis and wound healing applications. For the third section, we will pay specific attention to the proposed strategies for realizing effective mild PTT and the combined uses of low-temperature PTT and other cancer therapeutic modalities for achieving enhanced anticancer outcomes. Finally, we will list the current challenges faced in this field and propose some future research directions aiming at improving the existing strategies and developing new strategies for realizing low-temperature PTT.

2. Applications of Low-Temperature PTT

Less

2.1. Low-Temperature PTT for Treating Bacterial Infections

There are various kinds of pathogenic bacteria posing severe threats to human health, and the fight against the infections caused by these bacteria has become one of the most important biomedical directions for many decades [50]. Although the development of antibiotics has relieved the unfavorable condition to a considerable extent, we have not conquered bacterial infections fundamentally, especially in the situation where the bacteria have the staggering capability of mutation to adapt to extremely harsh environments resulting in the transformation to antibiotic-resistant bacteria. Additionally, many bacteria live in a sticky and multicellular community called biofilm which consists of plentiful biochemical molecules making an indispensable contribution to bacterial growth and reproduction [51]. The biofilms serve as a natural obstacle to prevent the invasion of life-threatening substances including antibiotics and some designed antibacterial nanomaterials. Accordingly, developing effective and practical methods able to surmount bacterial infections thoroughly is a challenging and urgent task.

PTT associated with nanotechnology has been well employed for antibacterial applications in recent decades, due to its broad-spectrum bacterial killing activity, avoidance of drug resistance, and satisfactory controllability. It is widely recognized that the mechanism of employing hyperthermia for killing microorganisms is destroying diverse life-fundamental molecules or structures, including protein denaturation, lipid evaporation, and cell membrane breakage [2, 52]. To date, many kinds of PTAs, such as carbon-based nanomaterials [53, 54], noble metal nanomaterials [55, 56], other metal-containing nanocomposites [57], and conjugated polymers [35, 36], have been used for antimicrobial applications and have established their unique advantages. Moreover, owing to the uneven heat distribution in the bacterial biofilms, it is difficult to completely eradicate the bacteria within the biofilms via PTT alone. In recent years, as shown in Table 1, an increasing number of related studies have demonstrated that the combination of low-temperature PTT and other therapeutic modalities including PDT and gas therapy or the combination of PTT and antimicrobial peptides (AMPs) or antibiotics has a remarkable performance in eliminating bacteria [58–61].

One of the most frequently used nanomaterials for PTT-based antibacterial application is PDA, which is formed by the self-polymerization of dopamine. PDA has been applied extensively in the biomedical field because of its high biocompatibility and facile functionalization. Furthermore, PDA nanomaterials possessing fascinating NIR photothermal conversion efficiency are excellent PTAs that can address numerous issues including the treatment of bacterial infections. Hence, associating PDA with other components which can endow the assembled platforms with the capacity to facilitate the efficacy of low-temperature PTT has attracted tremendous attention. For instance, Fan et al. synthesized a novel nanoplatform composed of PDA NPs modified by magainin I (MagI), a typical antimicrobial peptide capable of preferentially interacting with the bacterial membrane, and thiolated poly(ethylene glycol) (PEG), a widely used biocompatible polymer employed to promote the NPs’ dispersity and stability in hydrophilic environments [58]. After being irradiated by NIR light for only 500 s, the NPs elevated the temperature to 45°C in the suspension of Escherichia coli (E. coli) and presented exciting competence in targeting and killing bacteria. This work emphasizes that the close interaction between bacteria and PTAs can facilitate the effect of low-temperature PTT. Similarly, Yuan et al. reported a nanoplatform to get rid of the tough bacterial biofilm with nitric oxide- (NO-) enhanced PDT and low-temperature PTT via employing mesoporous PDA (MPDA) with surface modification of L-arginine (L-Arg) and further adsorption of indocyanine green (ICG) (the resultant product was termed AI-MPDA NPs) [59]. In the presence of NO synthase (NOS) existing in most cells, L-Arg could serve as a biocompatible donor of NO which has potential in interfering with bacterial DNA to disturb the bacteria’s basic life activities. In the meantime, the reactive oxygen species (ROS) generated by ICG further oxidized NO to reactive peroxynitrite (ONOO⁻), consequently strengthening the PDT’s efficiency, which further triggered the subsequent catalysis of L-Arg to release NO gas. Moreover, because NO-enhanced PDT could prominently disrupt the bacterial membranes to make the bacterial cells in biofilms sensitive to hyperthermia, low-temperature PTT induced by MPDA effectively led to the death of susceptible bacteria and the destruction of biofilms. Thus, after being injected to the bacteria-infected tissue where biofilms were already formed and being exposed to the NIR light, the AI-MPDA NPs residing in the focal area increased the temperature to 45°C and successfully killed bacteria and eliminated biofilms without eliciting notable inflammatory responses in vivo (Figure 2(a)). Further, the authors also demonstrated that AI-MPDA NPs could evoke a rapid wound healing effect.

Besides PDA, a two-dimensional molybdenum disulfide (MoS₂) nanoflake (an NIR PTA) was also used by Huang et al. for defeating bacterial infections at mild temperatures [60]. The authors modified MoS₂ nanoflakes with positively-charged quaternized chitosan (QCS) (yielding QCS-MoS₂) to increase the dispersion stability and assist the MoS₂ nanoflakes to adhere onto the bacterial surface more tightly. Further, the authors loaded ofloxacin, an antibiotic, onto QCS-MoS₂. Under NIR light irradiation, the heat generated by QCS-MoS₂ rendered methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to ofloxacin at a low dose. The resulting nanoplatform (denoted as QCS-MoS₂-OFLX) exhibited outstanding MRSA bacterium eradication effect, proving that the combined low-temperature PTT and antibiotic therapy could alleviate the drug resistance of bacteria (Figure 2(b)). Similarly, by employing red phosphorus NPs to realize low-temperature PTT, Tan et al. demonstrated that low-temperature photothermal treatment could make MRSA susceptible to conventional aminoglycoside antibiotics [61]. In this example, through exploring the underlying mechanisms, the authors proposed that low-temperature PTT owned the advantages of conquering multidrug-resistant (MDR) bacterial infection by restraining the activity of 2-aminoglycoside phosphotransferase. Thus, low-temperature PTT may pave a new way for the elimination of MDR bacteria and the improvement of the antibiotics’ bactericidal effect.

2.2. Low-Temperature PTT for Promoting Wound Healing

In the past few decades, effectively promoting wound healing which is a common but complicated process in animals has been considered as an important task in the field of biomedical engineering. There exist several important problems in the wound healing issue, including bacterial contamination [62], chronic wound [63], and excessive wound healing [64]. Fortunately, with the deeper understanding of wound’s pathophysiology and the development of biomaterials, a myriad of novel strategies have been proposed and diverse materials have been introduced into the wound healing therapeutic platforms. However, as shown in Table 1, up till now, only a few studies utilized low-temperature PTT to improve the effectiveness of wound therapy and they all exhibited satisfactory performance in facilitating wound healing [65–68].

For example, to conquer bacterial infection and alleviate surrounding inflammation for effective wound treatment, Xu et al. synthesized a gold NP-decorated hydroxyapatite (Hap) nanorod and modified the surface of the nanorod with PDA [65]. Through controlling the working time of NIR laser, the authors found that this nanoplatform could achieve low-temperature PTT for killing bacteria. Besides, this nanoplatform exhibited peroxidase-like activity and was capable of catalyzing hydrogen peroxide (H₂O₂) to produce highly reactive hydroxyl radical (·OH), thus rendering bacteria more sensitive to mild heat. Importantly, the release of Ca²⁺ and PO₄³⁻ from Hap could facilitate the expression of tissue repairing-related genes and promote the formation of granulation tissue and collagen synthesis, which realized the rapid tissue regeneration and accelerated wound healing. Likewise, Li et al. fabricated a Hap/nitrogen-doped carbon dot- (NCD-) modified graphene oxide (GO) heterojunction (GO/NCD/Hap) film which showed the enhanced photocatalytic and photothermal effects [66]. Under NIR light irradiation, this film could not only achieve PDT and mild PTT for killing bacteria but also repair vascular injury via the Ca²⁺-activated PLCγ1/ERK pathway and avoid excessive inflammation by activating the PI3K/P-AKT pathway to promote wound healing. The above two studies both verify that the employment of low-temperature PTT can help to eliminate bacteria and facilitate wound healing, and demonstrate that Ca²⁺ plays a crucial role in regulating tissue regeneration.

Besides wounds with bacterial infections, there are other types of wounds like chronic wounds which also need to be treated with. Lately, it has been found that the presence of both appropriate mild heat and bioactive elements can elevate the vascular density of granulation tissue and achieve satisfactory wound healing promotion, which is known as “hot spring” effect [69]. Inspired by this fact, Sheng et al. prepared a new photothermal hydrogel using oxidized sodium alginate, N,O-carboxymethyl chitosan (NOCS), and fayalite (FA) composed of Fe²⁺ and SiO₄⁴⁻ (Figure 2(c)) and evaluated the wound healing effect of this hydrogel by using full-thickness excisional wound model in diabetic mice [67]. Under mild NIR laser, the hydrogel showed satisfactory low-temperature photothermal effect and successfully released ferrous and silicate ions nearby the wound in vivo (Figure 2(d)). It was verified that the combination of mild heat and bioactive ions could promote endothelial cell proliferation and angiogenesis through activating different angiogenic factors and signaling pathways, finally realizing wound healing and tissue reconstruction. This example further emphasizes that some bioactive ions significantly contribute to wound healing and mild PTT can enhance the therapeutic effect of these bioactive ions. Therefore, the combination of bioactive ion-mediated treatment and low-temperature PTT may provide a new way for repairing chronic wounds under mild conditions.

Moreover, given that mesenchymal stem cells (MSCs) have the advantages of ease of isolation and expansion, great proliferative capability, multidirectional differentiation capacity, and immunomodulatory property [70, 71], MSC-based therapies have attracted increasing interest from many researchers working on the treatments of different kinds of diseases, like wounds [71] and cancer [72]. It has been found that both the MSC-induced vascular endothelial growth factor (VEGF) production and the MSC-involved collagen deposition can make contribution to skin tissue regeneration for wound healing [73]. Additionally, it is reported that copper has the potential in not only stimulating cell proliferation [74] but also boosting angiogenesis [75]. Recently, Xiao et al. used CuCl₂⋅2H₂O and bovine serum albumin (BSA) to construct ultrasmall CuS@BSA NPs via a biomineralization strategy in aqueous solution at a physiological temperature [68]. They isolated MSCs from the bone marrow of newborn mice. On the one hand, the CuS@BSA NPs showed the ability to induce MSCs to differentiate into fibroblasts. On the other hand, under NIR laser irradiation, the mild heat generated by CuS@BSA NPs which owned the photothermal conversion property also promoted the differentiation of MSCs. Furthermore, the authors encapsulated MSCs (preheated or not) with or without CuS@BSA NPs into Matrigel and seeded the mixture in the wound area to evaluate the wound healing efficacy of these therapeutic platforms. They found that in the presence of CuS@BSA NPs, both the MSCs preheated by a 42°C water bath and the MSCs in situ treated by mild heat generated by CuS@BSA NPs under NIR light irradiation showed the satisfactory capacity in differentiating into fibroblasts. The in vivo experimental results further demonstrated that the combination of CuS@BSA NPs and mild heating (preheating or in situ heating through NIR light irradiation) could enable MSCs to promote wound healing (Figure 2(e)). This work suggests that mild hyperthermia may be able to control the direction of MSC differentiation to some extent, and provides a novel strategy, i.e., the employment of low-temperature PTT, for improving MSC-based therapies for treating other diseases.

Although there are only limited studies paying attention to employing mild PTT to facilitate wound healing, we have obtained new insights into the synergistic utilization of low-temperature PTT and other therapeutic agents/strategies for wound treatments. These published examples may inspire more researchers to introduce other types of functional materials and alternative approaches into the mild PTT systems for more efficient and durable wound healing.

2.3. Low-Temperature PTT for Cancer Treatments

Cancer therapy has always been an extremely tough task since the advent of modern biology and medicine. In the past few decades, PTT for cancer treatments has achieved great improvement and showed good therapeutic performance with advantages of controllable administration, minimal invasiveness, and reduced side effects [1]. However, as mentioned above, there are diverse problems in desperate need to be solved in this region. Mild-temperature PTT has been recently recognized as a robust approach that can meet the requirement of defeating cancer with alleviated side effects. With the help of nanotechnology, more and more engineered therapeutic platforms can be orchestrated, such as those with stimulus-responsive characteristic for improving the therapeutic accuracy and those integrated with other functional molecules or motifs through a series of manufacturing methods for the accomplishment of multimodal cancer theranostics. As illustrated in Table 2 (which summarizes the common strategies for low-temperature cancer PTT) and Table 3 (which summarizes some typical examples that combine low-temperature PTT with other therapeutic modalities), there have been some smart and promising strategies to control the temperature during cancer PTT, which will be elaborated below.

2.3.1. HSP Downregulation/Starvation Therapy

HSPs, a highly evolutionarily conserved group of chaperone proteins that can be observed in cells exposed to elevated temperatures, are found to be extremely important in the folding, maintenance of structural integrity, and appropriate regulation of a series of cytosolic proteins, especially under the stressful circumstances [76, 77]. Classified by their molecular mass with the kDa unit, HSPs are usually divided into small HSPs (

molecular mass < 40 kDa

), and the HSP60, HSP70, HSP90, and HSP100 families [47]. Unfortunately, in the past few decades, numerous studies have proven that HSPs, especially HSP90 and HSP70 families, can significantly help cancer cells cope with harsh environments, enabling the survival of cancer cells [76, 78]. Regarding HSP90 capable of maintaining the conformation, stability, and function of key client proteins related to oncogenic signal transduction (i.e., mutant epidermal growth factor receptor), angiogenesis (i.e., VEGF), antiapoptosis (i.e., AKT), and metastasis (i.e., matrix metalloproteinase 2 and CD91), processes important for maintaining the cancer phenotype, it is substantially expressed at 2- to 10-fold higher levels in tumor cells compared to their normal counterparts, suggesting that it may be crucial for tumor growth and/or survival [76, 79–81]. Similarly, in normal cells, proteins of the HSP70 family are mainly expressed under stressful conditions and there are also some constitutively expressed HSP70 proteins to maintain cellular homeostasis. In contrast to normal cells, it has been found that some proteins of HSP70 family are fundamentally overexpressed in malignant human tumor cells of various origins for tumor growth and survival [77, 82]. With its working mechanism being extensively investigated, HSP70 has been suggested to be highly relevant to apoptosis through not only interfering with the intrinsic pathway based on the successive activation of caspases [78] but also inhibiting caspase-independent apoptosis [82, 83] and lysosomal membrane permeabilization [84], resulting in the escape of cancer cells from programmed cell death. Consequently, the downregulation of HSPs has been regarded as an alternative strategy for cancer treatment, and plenty of studies have suggested that the inhibition of HSPs can give rise to tumor suppression [85–87]. Since hyperthermia can trigger the overexpression of HSPs, which is the vital reason for the thermoresistance of cancer cells, it is reasonable to associate HSP downregulation with PTT to achieve high-performance low-temperature PTT. Inspiringly, the prosperity of nanotechnology has pushed HSP inhibition-mediated mild PTT to an unprecedented climax. Herein, we divide the well-known strategies of HSP suppression into two types, i.e., the use of HSP inhibitors and cancer starvation therapy, and will introduce the corresponding action mechanisms and related advancements in the following parts.

(1) HSP Inhibitors. With a deeper understanding of HSPs at the cell and molecular biology level, researchers encountered the advent of some highly specific HSP inhibitors and successfully employed them to experiments. For example, the benzoquinone ansamycin geldanamycin and 17-allylaminogeldanamycin were identified and put into clinical trials many years ago [88, 89]. Lately, scientists also found several other HSP inhibitors, represented by gambogic acid (GA), and figured out the mechanism at the molecular level [81, 90]. GA, a universally used HSP90 inhibitor which can weaken thermoresistance and induce apoptosis of cancer cells, has been applied in clinical and preclinical trials. With the development of genomics, small interfering RNA (siRNA) HSP inhibitors exerting their activity on transcription have attracted considerable attention [91, 92]. However, similar to chemotherapeutic drugs, the utility of HSP inhibitors still faces some problems, such as wide body distribution, low bioavailability, and unsatisfactory pharmacokinetics. To cope with the dilemma, as mentioned above, changing the formulation of a delivery system through nanotechnology and combining HSP inhibitors with other treatment methodologies have shed new light on these issues.

Small-Molecule HSP Inhibitors. Up till now, scientists have taken advantage of dozens of the existing nanomaterials to endow mild-temperature PTT platforms containing small-molecule HSP inhibitors with increased drug loading capacity and decreased nonspecific cytotoxicity. For example, Yang et al. proposed a facile method to synthesize a PEGylated one-dimensional coordination polymer via a one-step reaction and phase transfer [93]. ICG (an NIR dye), poly-L-histidine-PEG (pHis-PEG), and Mn²⁺ (a frequently used contrast agent in magnetic resonance (MR) imaging, MRI) were first self-assembled to build a three-dimensional porous framework in the methanol solution via coordination interaction, and after being transferred into the aqueous solution, the three-dimensional porous materials finally became one-dimensional nanofibers. Then, the authors integrated GA into the nanofibers to afford Mn-ICG@pHis-PEG/GA (Figure 3(a)) and uncovered that this nanoplatform could prominently facilitate cancer cell apoptosis and realize efficient low-temperature PTT. Moreover, the nanoplatform showed enhanced cell internalization and tumor retention due to its pH-responsive ability, which was attributed to the protonation of imidazole groups in pHis-PEG under the acidic environment. Recently, our group established an intelligent molecular targeting-mediated nanoplatform composed of GA, dc-IR825 (a fluorescent probe and a PTA), and human serum albumin (HSA) (a biocompatible carrier for hydrophobic molecules) [27]. The nanoplatform (HSA/dc-IR825/GA NPs) showed intrinsic low pH-induced charge reversal which was beneficial for the notably increased cellular uptake and tumor accumulation under the acidic tumor microenvironment (TME). It was found that the NPs were well located in mitochondria after endocytosis. Under NIR light irradiation, the ROS generated by dc-IR825 in the NPs effectively destructed mitochondrial membranes, which resulted in the escape of GA from the mitochondria to the cytoplasm and subsequent HSP90 inhibition for low-temperature PTT (Figure 3(b)). Additionally, we have also demonstrated that the nanoplatform could realize synergistic low-temperature PTT/GA-mediated molecularly targeted therapy (MTT) in vivo and efficiently eliminate tumors and inhibit tumor metastasis. In another example, Li et al. fabricated zeolitic imidazole framework-8 (ZIF-8) NPs and embedded bismuth nanodots in the ZIF-8 NPs (abbreviated as BZ) by a simplified one-step reduction method [94]. This composite nanomaterial possessed satisfactory photothermal conversion efficiency in the NIR-II (1000–1350 nm) region, which was important for realizing deep tissue penetration. The authors further loaded GA onto BZ to afford GBZ, and demonstrated that GBZ could achieve markedly accelerated GA release under acidic conditions and NIR light exposure. Moreover, the authors revealed that GBZ could successfully treat hepatocellular carcinoma in mouse models. These studies all emphasize that GA-containing nanoplatforms can remarkably alleviate the thermal resistance of cancer cells and induce cancer cell apoptosis for enhanced low-temperature PTT. Moreover, the low pH-responsive property of nanomaterials is crucial for realizing specific tumor accumulation and/or GA release, which may inspire researchers to design more smart nanoagents with multiple exogenous and/or endogenous stimulus-responsive capacity for improving the performance of low-temperature PTT systems.

Recently, Sun et al. proposed a novel one-pot synthesis method for fabricating hollow mesoporous carbon spheres (HMCSs), which had the eminent potential in photothermal conversion and photoacoustic (PA) imaging (PAI) [95]. After PEG modification and GA loading, the resultant HMCS-PEG-GA displayed its capacity in ablating tumors under moderate temperature environments controlled by the NIR laser. Semiconducting polymer NPs and black phosphorus quantum dots have also been employed to encapsulate GA for promoting the efficiency of PTT under mild NIR light irradiation [96, 97]. In addition, the Chen group fabricated a scaffold to achieve low-temperature PTT of breast cancer. They first synthesized poly(acrylic acid)-g-poly(lactic acid) (PAA-g-PLLA) and then connected PAA-g-PLLA with graphene oxide (GO) via a low-pH cleavable bond, forming GO-PAA-g-PLLA [98]. After GA was loaded to GO-PAA-g-PLLA, the obtained complex could release GO/GA in the acidic TME due to the low-pH cleavable bond for mild PTT. Further, poly(caprolactone) (PCL) was employed as the framework to form the final GO-GA-polymer scaffold via mixing PCL with GA-loaded GO-PAA-g-PLLA. The scaffold-mediated low-temperature PTT could effectively achieve tumor eradication both in vitro and in vivo. The authors then inserted adipose-derived stem cells into the interspace of the scaffold to deliver the stem cells for adipose tissue regeneration at the site of breast cancer, finally realizing reconstruction of breasts after surgical resection. This work provides a promising strategy for the combination of tumor ablation and tissue regeneration under gentle hyperthermia.

Besides GA, there are many other small-molecule HSP inhibitors that have been employed in low-temperature PTT for achieving satisfactory cancer treatment outcomes. For example, Yang et al. employed quercetin (Qu) as a multifunctional element to connect with ferrous iron (Fe^II) and polyvinylpyrrolidone (PVP) via coordination interaction to prepare nanodrugs (denoted as Qu-Fe^IIPs) [99]. Qu had several important roles in this nanosystem: First, it is an inhibitor of HSP70 for realizing mild hyperthermia under NIR light irradiation [100]. Second, since quercetin possesses good ROS-scavenging ability, the Qu-Fe^IIPs could clear excessive ROS which might endanger surrounding healthy tissues, and reduce ROS-induced inflammatory cytokines to avoid unexpected inflammation [99]. Meanwhile, the coordination between Qu and Fe^II became loose when Qu was oxidized by ROS, and subsequently Qu-Fe^IIPs were disassembled into ultrasmall NPs (Figure 3(c)), which led to rapid renal clearance of the NPs to minimize acute or chronic toxicity. This study highlights the advantage of using Qu for constructing nanomaterials for mild PTT.

17-Allylamino-17-demethoxygeldanamycin (17-AAG, also termed tanespimycin), another common HSP90 inhibitor, has also been applied for constructing low-temperature PTT systems. For example, Luo et al. loaded 17-AAG into a well-designed micelle (named as CA-Micelle) composed of PEG₁₁₄-PCL₆₀ (in which PCL is the abbreviation of poly(ε-caprolactone)) and cypate, one of the cyanine dyes capable of yielding hyperthermia under NIR light irradiation [101]. Because cypate could also produce ROS under NIR light irradiation, the micelles achieved the cytoplasmic translocation of 17-AAG to interact with HSP90 by ROS-mediated ysosomal disruption. It was found that 17-AAG was capable of inhibiting antiapoptotic p-ERK1/2 proteins to promote early apoptosis for effective 17-AAG-mediated MTT and downregulating the expression of p-Akt to attenuate thermoresistance of cancer cells for realizing promoted low-temperature PTT (Figure 3(d)). Moreover, the late apoptosis was also enhanced due to the combination of PTT and MTT, thus leading to excellent tumor eradication effect. In another example, the Qian group entrapped VER-155008 which can restrict the activity of both HSP70 and HSP90 into methoxy PEG-poly(D,L-lactic acid) to form VER-155008 micelle to improve the water solubility of VER-155008 [102]. Then, this VER-155008 micelle was mixed with methoxy PEG-coated gold nanorod (AuNR) (serving as a PTA) to achieve the enhanced tumor depletion under mild temperature. In addition, 2-phenylethynesulfonamide (PES), famous for disturbing HSP70 activity via multiple cell signaling pathways with excellent specificity and negligible cytotoxicity, was introduced into a poly(3,4-ethylenedioxythiophene)- (PEDOT-) encapsulated thermoresponsive nanogel composed of poly(N-isopropylacrylamide-co-acrylic acid) (PNIPAM) by Liu et al. [103]. To meet the requirements of real-time diagnosis, Jiang et al. fabricated a flower-like NiS₂-coated NaLuF₄:Nd (Lu:Nd@NiS₂) NP for short-wave infrared light imaging and MRI-guided PTT through using epigallocatechin gallate (EGCG) that can suppress HSP90 activity [104]. This NP showed satisfactory antitumor efficacy via low-temperature PTT and could be employed as an outstanding theranostic nanoplatform. Recently, Zhang et al. adopted BIIB021, an HSP90 inhibitor, to prepare a novel mild-temperature PTT platform by first synthesizing PEG-IR780 (IR780 is an NIR cyanine dye) via covalent conjugation between PEG-SH and IR780 and then adding BIIB021 to obtain PEG-IR780-BIIB021 nanomicelles via the solvent evaporation method [105]. The authors demonstrated that the positively charged NIR PTA IR780 could selectively accumulate in cancer cell mitochondria where the membrane potential is higher than that of normal cell mitochondria, thus realizing effective mitochondrion-targeted cancer therapy. Moreover, the nanomicelles located in the mitochondria of the cancer cells generated heat and released BIIB021 to reduce the tumor cell resistance to mild hyperthermia after NIR light irradiation, leading to the decrease of mitochondrial membrane potential and quick release of crucial intrinsic apoptotic factors to activate the mitochondrial apoptotic pathway for achieving high-performance low-temperature PTT. Due to the potential of BIIB021 in conquering breast cancer possessing overexpressed HSP90, this nanomicelle exhibited promising capacity for mild PTT of breast cancer.

The above examples highlight that the integration of small-molecule HSP inhibitors (including GA, Qu, 17-AAG, VER-155008, PES, EGCG, and BIIB021) into PTT nanoplatforms represents an important strategy to deepen our understanding of the working mechanism of PTT and achieve the safe and effective tumor ablation via low-temperature PTT.

siRNA HSP Inhibitors. In the past few years, siRNAs have shown great potential for low-temperature PTT because some of them can downregulate HSPs at the genetic level through gene silencing. The siRNAs against HSPs are capable of interacting with the messenger RNAs (mRNAs) of HSPs via complementary base pairs, and then, RNA-induced silencing complexes are formed to cut mRNAs into small pieces, thus inhibiting the expression of HSPs [106–108]. However, there are diverse biomolecules including nucleases in the blood stream able to degrade naked nucleic acids during the delivery process [109]. Furthermore, nucleic acids must escape from endosomes before the endosomes fuse with lysosomes containing various enzymes that can inactivate or degrade foreign molecules. To this end, Wang et al. embedded siRNAs against HSP70 into the pores of cypate-conjugated upconversion nanocomposites for mild photothermal ablation of tumors with the assistance of upconversion luminescence imaging and MRI [106]. Given that gold nanostructures possess advantages of versatile nucleic acid conjunction, satisfactory photothermal conversion efficiency, and acceptable biosafety, Wang et al. utilized gold to construct nanoshells, which were modified with siRNAs against HSP70 to make the cancer cells more susceptible to moderate hyperthermia [107]. In another example, Ding et al. fabricated an anti-Hsp70 siRNA (siHsp70) delivery platform, which possessed three shields to protect siRNA [108]. First, siHsp70 and DNA-grafted PCL (DNA-g-PCL) were assembled into nanogels by nucleic acid hybridization. Second, PDA was employed to form a thin layer attached on the surface of the above-obtained nanogels, which introduced photothermal conversion capability to the whole nanoplatform. Third, after surface PEGylation, the nanoplatform (denoted as PP-NG) (Figure 3(e)) displayed elevated physiological stability and inhibited the degradation of siRNAs by ribonuclease (RNase) A. Moreover, it was found that in the acidic environments of endosomes or endolysosomes which encapsulated PP-NGs, the oligomer PDA would degrade and detach from the PDA layer of PP-NGs, thus facilitating the release of nanogels from PP-NGs and inducing the nanogels to be exposed to the enzymes. Further, under NIR light irradiation, the PDA-mediated hyperthermia could help the nanogels escape from endolysosomes to the cytoplasm where they could be degraded by RNase H (which recognizes DNA-RNA hybrid duplex and digests the RNA strand), and then, siRNAs were released to the cytoplasm to downregulate HSP70 to realize effective low-temperature PTT (Figure 3(f)). This work exemplifies a feasible solution to realize safe siRNA delivery for low-temperature PTT.

(2) Cancer Starvation Therapy. Lately, cancer starvation therapy has been introduced for the ablation of malignant tumors [110]. As is well known, tumors display fast nutrition consumption to maintain the rapid speed of cancer cells’ growth and proliferation. On the one hand, cancer cells secrete several proangiogenic growth factors and express the counterpart receptors of the factors. Therefore, there are abundant blood vessels around and inside tumors that ensure the tumors’ sufficient nutrition supply for their survival and growth. On the other hand, cancer cells tend to obtain energy by an abnormal type of metabolism (the Warburg effect) that mainly sustains energy supply through anaerobic glycolysis, which exacerbates their reliance on glucose [111]. Hence, two major principles of designing platforms for cancer starvation therapy have been proposed [110]: (1) inhibiting angiogenesis or blocking tumor blood vessels and (2) reducing the cellular uptake of or exhausting life-necessary nutrients, especially glucose. Unfortunately, starvation therapy only partially succeeds due to a series of obstacles like increased tumor hypoxia, unsatisfactory targeting capacity, induced drug resistance, and elevated tumor metastasis risk, which all impede their further applications in clinic [110]. To overcome these challenges (or some of these challenges), combining starvation therapy with PTT serves as a good choice since it can maximize the anticancer therapeutic efficiency [110, 112]. More importantly, given that both the production of HSPs and the execution of their bioactive processes need ATP, developing strategies that can lead to the lack of ATP via blocking or decreasing the supply of energy sources like glucose provides an efficacious way to realize HSP inhibition and hence mild-temperature PTT. Therefore, cancer starvation therapy represents one promising strategy that can be combined with low-temperature PTT to achieve potentiated anticancer effect.

Considering that there are overexpressed glucose transporters on the membranes of tumor cells, blocking or downregulating these transporters acts as an emerging solution to deprive cancer cells of cytoplasmic glucose for cancer starvation therapy. This strategy has been employed for enhanced mild PTT. For example, Chen et al. used diclofenac (DC), which served as a small-molecule inhibitor of Glut1 (one of the major glucose transporters (Gluts)), and hyaluronic acid- (HA-) modified plasmonic gold nanorod (GNR) to construct GNR/HA-DC for realizing low-temperature PTT [113]. As some cancer cells overexpress CD44 receptors capable of interacting with HA and TME is highly abundant in hyaluronidase (HAase), this platform could target CD44-overexpressed tumors and achieve the HAase-mediated release of DC to the cytoplasm to inhibit Glut1. Thanks to its surface plasmon resonance property, GNR/HA-DC exhibited noticeable photothermal conversion capacity, which was beneficial for realizing cancer-specific mild-temperature PTT especially for CD44-overexpressed tumor cells (Figure 4(a)).

Moreover, glucose oxidase (GOx), which can catalyze glucose, O₂, and H₂O into gluconic acid and H₂O₂, has been widely used in cancer therapy [114–116]. In the past few years, due to the ability of GOx to achieve cancer starvation, some researchers utilized GOx to realize low-temperature PTT of tumor [32, 117, 118]. For instance, a nanoreactor was prepared by Cao et al. to combine tumor starvation therapy with multiple mechanism-enhanced mild-temperature phototherapy for cancer treatment [117]. They loaded both GOx and ICG onto the Fe-doped polydiaminopyridine (Fe-PDAP) nanozyme via electrostatic adsorption and

π

π

interaction to obtain the Fe-PDAP/GOx/ICG nanoreactor. On the one hand, the Fe-PDAP nanozyme could catalyze H₂O₂ produced during GOx-mediated glucose consumption as well as supplied by tumor cells into O₂ to improve O₂-dependent ICG-based PDT. On the other hand, the Fe-PDAP nanozyme was capable of depleting GSH (which is the key antioxidant agent capable of reducing ROS) by a metal-reducing reaction after releasing Fe³⁺, thus further enhancing the efficiency of PDT. Meanwhile, under NIR light irradiation, mild PTT was achieved due to GOx-mediated HSP downregulation and ICG-based hyperthermia. To be noted, the Fe-PDAP/GOx/ICG showed satisfactory performance in multimodal fluorescence imaging (FLI)/PAI/MRI. This work verifies that the GOx-mediated cancer starvation therapy has advantages in not only downregulating HSPs for low-temperature PTT but also remarkably improving the synergistic cancer therapeutic efficiency. However, protecting GOx from deterioration and leakage during the circulation and endocytosis processes to execute catalysis validly is a disturbing problem. To deal with this issue, researches have designed a variety of GOx-containing nanomaterials and further optimized the GOx release process by the introduction of stimulus responsiveness [32, 118]. Zhou et al. entrapped GOx into a porous hollow Prussian blue (PB) NP (termed PHPBN) which is a biologically friendly NIR PTA and can protect GOx from being inactivated [118]. Further, they conjugated the surface of GOx-loaded PHPBNs with HA through disulfide bonds, which can be cleaved by intracellular glutathione (GSH) to realize the GOx release into the cytoplasm, and meanwhile, the HA can help the nanoplatform to target the CD44 receptors overexpressed on the plasma membranes of HepG2 cells. Finally, PEG was grafted to the outer shell to prolong the blood circulation time. Importantly, the PHPBNs were able to catalyze H₂O₂ generated during GOx-mediated glucose oxidation to produce oxygen for alleviating tumor hypoxia and elevating the catalytic efficacy of GOx, finally achieving effective cancer starvation therapy and low-temperature PTT. In another example, our group prepared thermosensitive liposomes which were loaded with GA, GOx, and ICG to afford GOIGLs [32]. Upon NIR light irradiation, ICG within the liposomes could efficiently convert light to heat, and when the temperature was elevated to above 42°C, the liposomes underwent the gel-to-fluid phase transition and subsequently released the loaded GA, GOx, and ICG (Figure 4(b)). Additionally, under visible light illumination (400–750 nm), H₂O₂ which was produced during the GOx-catalyzed glucose oxidation reaction could be transformed into ⋅OH, which is one of the most lethal ROS to cells, thus showing enzyme-enhanced phototherapy (EEPT) effect. Besides, after NIR light irradiation, the GOIGLs could successfully escape from lysosomes via ROS-mediated lysosomal disruption, which contributed to the release of GOx and GA to the cytoplasm to consume glucose and downregulate HSPs, respectively, thus realizing synergistic starvation therapy and low-temperature PTT (Figure 4(c)). This work emphasizes the robust anticancer therapeutic effect of the combined use of HSP inhibitor-promoted mild PTT and GOx-mediated cancer starvation therapy. Besides GOx, GOx-like nanoagents can also be used to construct the starvation therapy/mild PTT-based platforms for defeating cancer. As an example, Tang et al. fabricated a two-dimensional MnO₂ nanosheet (M-NS) through a unique one-step wet-chemical method, which could control the size and thickness of M-NSs by adjusting the ratio of BSA to MnCl₂ in oxygen-containing alkaline solutions [119]. Moreover, the M-NSs exhibited excellent GOx-like catalytic performance and NIR-absorbing ability. Thus, the M-NSs could consume intracellular glucose leading to the downregulation of HSPs and generate heat under NIR light irradiation, finally achieving low-temperature PTT (Figure 4(d)). The authors also developed a novel sono-chemical way to coat the surface of M-NSs with 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-modified BSA (BSA-NOTA) and found that the modified M-NSs possessed improved stability and accessibility of further functionalization, such as chelation with radioactive ⁶⁴Cu for positron emission tomography imaging. The above reports all utilize the advantages of GOx or its mimics to construct cancer therapeutic nanoplatforms and emphasize the eminent potential of GOx/GOx mimics-mediated tumor starvation in promoting effective low-temperature PTT.

Besides employing the Glut inhibitors and GOx, Dang et al. exploited a new way to accomplish synergistic cancer starvation therapy/low-temperature PTT. The authors used an siRNA against pyruvate kinase M2 (siPKM2, which is capable of interfering with tumor glycolysis) and ICG to fabricate a novel nanocomplex based on a spherical dendrimer polypeptide (DPP) [120]. Specifically, amine-terminated polyamidoamine (PAMAM) was utilized as a macroinitiator template to synthesize DPP via controlled ring-opening polymerization (ROP) of N-carboxyanhydride followed by side-chain functionalization with guanidines. The DPP could load ICG into its hydrophobic cavity, and meanwhile, siPKM2 was condensed by DPP via electrostatic interaction to form positively charged nanocomplexes. Further, to improve the stability and biosafety, the nanocomplexes were enveloped by human serum albumin to obtain the final product termed D-I/P@HSA NCs (NCs: nanocomplexes). Under NIR light irradiation, the NCs exhibited enhanced tumor photothermal ablation efficiency by the aid of the siPKM2-mediated cancer starvation effect. This research points out that disturbing tumor glycolysis via molecular or nanoscale agents may represent a novel approach to realize the combination of cancer starvation therapy and low-temperature PTT.

2.3.2. Autophagy-Mediated Cancer Therapy

Autophagy, an essential catabolic process, can degrade and recycle misfolded proteins or damaged organelles to conserve cellular homeostasis [121]. Nevertheless, there have been arguments about the role of autophagy in the occurrence and progression of cancers. On the one hand, autophagy can accelerate tumor development and shield cancer cells from diverse cellular stresses like chemical drugs and radiation, eventually making tumors develop chemo- and radioresistance and be difficult to be cured [122–125]. On the other hand, autophagy can restrict tumorigenesis via regulating many oncogenes and tumor suppressor genes and inhibit tumor invasion and metastasis from the primary sites via limiting necrosis and inflammation [122–124]. Thus, both the promotion and inhibition of autophagy have been applied to defeat cancers.

Given that inhibition of autophagy may contribute to tumor eradication, researchers have recently invented many approaches to inhibit autophagy for improved cancer treatments [126–128]. Among these approaches, the combination of autophagy-modulating molecules and mild PTT shows the satisfactory ability of eliminating tumors at gentle temperatures [129–132]. Some studies have figured out that low-temperature PTT can induce both apoptosis and autophagy in cancer cells, and autophagy provides a survival way for malignant tumors [129, 130]. Further, it has been revealed that the inhibition of autophagy can augment apoptosis and apparently strengthen the efficiency of PTT, verified by the lifted malignant cells’ fatality under mild hyperthermia using the autophagy inhibitor chloroquine (CQ) [129] and chloroquine diphosphate-loaded NPs [130]. It is noteworthy that the research carried out by Zhou et al. is the first report of using CQ-mediated autophagy inhibition to enhance PTT [129]. The authors loaded CQ on the surface of PEG-modified PDA NPs (the resultant product was termed PDA-PEG/CQ NPs) and found that CQ could be released from PDA NPs in the moderately acidic environment (

pH = 6

). The authors demonstrated that this nanoplatform could realize effective CQ release in the TME and cytoplasm to inhibit autophagy, leading to the elevated cancer cell sensitization to mild PTT for defeating cancer (Figure 5(a)). Lately, Shao et al. synthesized a rattle-structured NP by encapsulating a PDA nanocore in a hollow mesoporous silica nanoshell to afford PDA@hm [131]. Then, CQ was loaded into the hollow cavity of PDA@hm and GOx was conjugated onto the surface of the above obtained NP, thus obtaining PDA@hm@CQ@GOx (Figure 5(b)). It was demonstrated that this nanoplatform could successfully achieve enhanced photothermal eradication of tumors under the moderate temperature with the assistance of GOx-mediated starvation and CQ-mediated autophagy inhibition, consequently reducing cancer survival rates (Figure 5(c)). Additionally, the CQ-mediated autophagy inhibition made contribution to compensating for the loss of mild PTT and starvation therapy efficacies due to PTT- and starvation-activated autophagy, showing the outstanding synergistic effect of the PDA@hm@CQ@GOx. Moreover, the nanoplatform was capable of realizing PAI. This trimodal synergistic treatment strategy (i.e., autophagy inhibition, starvation therapy, and mild PTT) has a great potential in overcoming PTT’s side effects and elevating the efficiency of low-temperature PTT. Recently, to break the cycle between tumor cell proliferation and bone resorption (this cycle plays an important role in the promotion of bone tumors’ progression and metastasis), Wang et al. fabricated PEG-conjugated alendronate-functionalized and CQ-loaded PDA NPs (PPA/CQ) for bone cancer therapy [132]. It was found that, owing to the alendronate, PAA had the advantage of strongly interacting with hydroxyapatite abundant in bone tissues, thus realizing the bone-targeting function. Besides facilitating the PDA-mediated photothermal ablation of bone tumors at mild temperatures, CQ could also attenuate tumor-associated bone resorption via interfering with the differentiation and activation of osteoclasts and subsequently inhibiting osteoclastogenesis. The in vivo experiments showed that the PPA/CQ nanoplatform achieved both tumor elimination and osteolysis inhibition. This work verifies that CQ-mediated autophagy inhibition provides a feasible method for malignant bone tumor treatments.

On the other hand, the augment of autophagy in cancer cells has also been exploited to be combined with mild PTT for defeating tumors. Zhou et al. fabricated a PEGlyated melanin-like PDA NP decorated with a cyclic Arg-Gly-Asp (RGD) peptide which is famous for binding integrin overexpressed in tumor tissues, and a beclin 1-derived peptide (denoted as beclin 1) which is the product of a putative gene related to the upregulation of autophagy [133]. As expected, the NPs showed tumor-targeting capability and enhanced low-temperature PTT efficiency (resulting from the promotion of autophagy) (Figure 5(d)).

Collectively, the above examples highlight that we must pay more attention to figuring out and utilizing the complicated relationship between mild PTT and autophagy regulation to elevate the efficiency of tumor eradication.

2.3.3. Organelle-Targeting Strategy

Undoubtedly, the integrity of the structure and function of all cellular organelles is the crucial support for cell growth and proliferation, and it is also of great significance in the invasion and metastasis of cancer cells [134, 135]. It is worth noting that a large number of studies have attached great importance to developing biomedical engineering platforms with awesome organelle-targeting capacity for bothering or even devastating the organelles and finally deteriorating tumors [24, 25, 30, 126, 136–139]. Most of the organelles are very susceptible to elevated temperatures, especially the cell nucleus enveloping approximately all the genetic materials easy to denaturation, which brings hope to low-temperature PTT. On the other hand, there are numerous pores consisting of nuclear pore complexes (NPCs) on the nucleus envelop, playing an important role in facilitating substance transportation and signal conduction between the nucleus and cytoplasm. Numerous studies spared no effort to develop highly reliable and effective drugs or delivery systems possessing the capability of taking action in the nucleus following passing through these tiny pores. For instance, Cao et al. engineered a cell nucleus-targeting TAT peptide onto the surface of a vanadium carbide quantum dot to obtain V₂C-TAT, which could serve as a robust NIR-II PTA [140]. After encapsulating V₂C-TATs into RGD peptide-decorated endogenous exosomes which were beneficial for the elevated biocompatibility, nonimmunogenicity, and long blood circulation ability, the authors found that the nanosystem could gather nearby the tumor and enter the nucleus to destroy the genetic materials directly for low-temperature PTT with the dual guidance from PAI and MRI. Similarly, our group found that the palladium nanosheets modified by TAT (Pd-TAT) mainly accumulated in the perinuclear region and showed increased endocytosis and reduced efflux [14]. Importantly, Pd-TAT in the perinuclear region could trigger the overexpression of lamin A/C proteins to elevate nuclear stiffness and inhibit cancer metastasis, because lamin A/C proteins are highly related to nuclear stiffness and lack of the proteins facilitates cell migration. Under mild NIR light irradiation, the Pd-TAT presented perinuclear-to-intranuclear translocation and exhibited enhanced cancer cell metastasis inhibition and low-temperature PTT effect. In addition, Liu et al. synthesized an ultrasmall chitosan-coated ruthenium(IV) oxide NP with excellent NIR-II photothermal conversion ability and suitability for PAI [141]. The NPs could accumulate in the cell nucleus and release mild heat enough for destroying nuclear DNA under NIR-II light irradiation. Jiang et al. synthesized an Hf-heptamethine indocyanine dye- (Hf-HI-4COOH-) based nanoscale coordination polymer (NCP) which possessed strong NIR absorption and excellent photothermal conversion capacity to serve as an intrinsic nucleus-targeting PTA [142]. Under low-power NIR light irradiation, the NCP could generate enough heat to destroy the nucleus at a mild temperature, leading to the elimination of cancer cells. This study expands the application of NCPs and provides a new choice for conducting nucleus-targeted low-temperature PTT (Figure 5(e)).

Additionally, mitochondrion which is considered as the cellular energy factory and apoptosis control center has been regarded as a key location where mild hyperthermia can achieve a satisfactory cancer cell killing effect. Based on this, Qiu et al. constructed mitochondrion-targeting lipophilic iridium(III) cation-modified Fe₃O₄ NPs [143]. The NPs not only showed superb MRI/photothermogenic ability but also worked as a nanozyme for executing the Fenton reaction by catalyzing H₂O₂ generated from the mitochondrial respiratory electron transport chain (this catalysis process could be stimulated by the heat stress of mild PTT) into ⋅OH for killing cancer cells, thus realizing excellent MRI-guided and nanozyme-mediated mild-temperature PTT. In addition, the cytoskeleton, which is highly related to tumor migration, is a proper target for a variety of therapeutics [144, 145]. Our group fabricated platinum-doped carbon NPs (CNPs) by a facile one-pot hydrothermal method and modified them with PEG to afford PEG-PtCNPs (Figure 5(f)) [145]. To observe the behaviors of PEG-PtCNPs both in vitro and in vivo, we conjugated rhodamine B isothiocyanate (RITC) onto PEG-PtCNPs to afford PEG-PtCNPs-RITC. The PEG-PtCNPs showed strong photothermal conversion ability and could bind to multiple organelles. Additionally, it was found that under mild NIR light irradiation, PEG-PtCNPs impaired the cellular cytoskeleton and induced the overexpression of lamin A/C, leading to the inhibition of tumor metastasis. When the cells were irradiated by the NIR laser at a higher power density, irrecoverable destruction to the nuclear membranes was observed and the nuclear delivery of PEG-PtCNPs in the absence of nucleus-targeting ligands was subsequently realized. Thus, this nanoplatform achieved the damage to the cytoskeleton and nucleus by multiorganelle-targeted PTT and showed exceptional performance in tumor ablation and metastasis restriction. This work provides a new solution for targeting multiple organelles to elevate the efficiency of low-temperature PTT.

2.3.4. Synergistic Therapy

Since numerous preclinic and clinic experiments have disclosed that many monotherapies show low efficiency in defeating tumor metastasis/reoccurrence and some adverse side effects like high toxicity to normal cells and damage to immune system during the past few decades, many researchers have devoted themselves to conquering these obstacles. The rational combination of conventional strategies has been appreciated as an important breakthrough verified by a myriad of studies, which has opened a new chapter in the field of cancer therapy [146].

As is well known, the presence of hypoxic cells in tumors is considered to be one of the main reasons for the reduction of the effectiveness of radiotherapy, certain chemotherapeutic drugs, and phototherapy [147], and the insufficient blood flow within tumor tissues impedes the delivery of various therapeutic agents [111]. Fortunately, the association of mild hyperthermia treatment with other therapeutic modalities has obtained many encouraging results. It was found that at a slightly higher temperature the tumor hypoxic environment can be ameliorated due to the accelerated blood flow [147–149]. Additionally, increased vascular permeability nearby the heated region can be observed, which may contribute to the enhanced permeability and retention (EPR) effect (the key of the passive accumulation of drugs in tumor tissues). Thus, low-temperature PTT, which can induce mild hyperthermia within tumors, may have considerable potential in improving the effects of other therapies. In the meantime, it has been widely recognized that NPs can passively accumulate in tumors due to the EPR effect and actively target tumors through being modified by some molecules or motifs capable of recognizing and interacting with tumors or TME [150]. Moreover, the utility of nanostructures consisting of PTAs and other agents like chemodrugs, radiosensitizers, and photosensitizers can integrate multimodal treatments in one nanoplatform. Therefore, with the assistance of nanotechnology, we can remarkably improve the cancer cell-killing performance of other therapies in combination with low-temperature PTT. On the other hand, other treatment results can sensitize cancer cells to be more vulnerable to mild heat, thus enhancing the tumor eradication effect of low-temperature PTT. Besides, low-temperature PTT possesses other unique advantages when it is combined with different therapeutic modalities, which will be discussed in the following parts.

(1) Chemotherapy. Chemotherapy, surgical resection, and radiotherapy (RT) are considered as the three major tactics for cancer treatments. Chemotherapy plays an important role in clinical cancer therapy and a large number of novel cancer therapeutic strategies and agents have been developed up till now [151–154]. Nevertheless, there are several problems that are desperately imperative to be solved, e.g., indiscriminative accumulation and cellular uptake leading to incomplete tumor eradication and unavoidable damage to normal tissues, the development of multidrug resistance (MDR) compromising the therapeutic performance of the chemodrugs, and unsatisfactory therapeutic effects of the drugs used at safe doses [155–157]. Thus, it is of great significance to develop a platform which can efficiently kill tumors at a relative low drug dose.

To date, an agreement has been reached that combining chemotherapy with PTT can make a practical contribution to improving the anticancer outcomes [158]. First, PTT may achieve spatiotemporally-controlled drug delivery by adjusting the location, power density, and working time of NIR/visible light. Second, hyperthermia can render cancer cells more accessible and vulnerable to chemotherapeutic drugs. Third, the heat generated by PTAs can stimulate the chemodrugs’ intratumoral penetration and accumulation due to increased tumor blood flow and vascular permeability. In addition, due to the reduced phototoxicity and enhanced stability of some chemodrugs at moderate temperatures, decreasing the temperature used to kill tumors by controlling light intensity, blocking HSPs, or interfering with other thermoresistance-related signal pathways makes the combined use of chemotherapy and mild PTT an appealing choice for cancer treatments. Furthermore, the administration of chemodrugs can compensate for the insufficient heat damage, thus realizing low-temperature PTT [159–177]. For instance, Sherlock et al. fabricated an ultrasmall nanocrystal (FeCo/GC) containing a single crystalline iron-cobalt core surrounded by a single- or few-layer graphitic carbon (GC) shell, which could serve as a PTA and an MRI contrast agent [159]. Further, doxorubicin (DOX) was loaded on the GC shell by

π

π

stacking interaction to form FeCo/GC-DOX. Under acidic conditions in TME and endosomes/lysosomes, the

π

π

stacking interaction was weakened, leading to the pH-sensitive release of DOX. Under NIR light irradiation, FeCo/GC-DOX exhibited enhanced cellular uptake, which was determined by MRI, DOX fluorescence measurements, and flow cytometry. The enhanced cellular uptake and the elevated chemotherapeutic efficacy of DOX under mild hyperthermia dramatically enhanced the toxicity of FeCo/GC-DOX toward breast cancer cells. Wang et al. also found that mild hyperthermia could help DOX to penetrate the extravascular space and transiently alter the tumor interstitial permeabilization by using DOX-loaded Gd-hybridized plasmonic Au nanocomposites [160]. The authors also confirmed that after further HA modification, the obtained nanocomposites could target CD44-overexpressing cancer cells and achieve drug release mediated by HAase, further leading to enhanced tumor elimination (Figure 6(a)). Besides, a large number of other PTAs, including hollow CuS NPs [161], Rb_xWO₃ nanorods [162], gold nanomaterials [163], black phosphorus nanosheets [164], PDA NPs [165, 166], ICG or polypyrrole- (PPy-) containing nanomaterials [166–169], and hollow mesoporous organosilica nanocapsule [170], have been employed to cooperate with various clinical chemotherapeutic drugs, such as paclitaxel, docetaxel (DTX), and gemcitabine, to realize synergistic low-temperature PTT/chemotherapy.

Drug-resistant cancer cells tend to express a series of membrane transporters represented by the ATP-binding cassette transporter (ABC) family to export diverse cytotoxic drugs, and in the meantime induce the mutation of proapoptosis genes like TP53 to escape from apoptosis, then resulting in the elevation of their endurance to the therapeutic agents. Fortunately, it is reported that the mild heat produced by PTAs may bring us encouraging hope. Wang et al. found that the moderate heat produced by AuNR-based mesoporous silica nanocarriers (Au@SiO₂) under the 780 nm femtosecond pulsed laser irradiation (3.2 W cm⁻², 10 min) not only evoked the obvious and long-lasting expression of the heat shock factor-1 (HSF-1) capable of restricting the NF-κB pathway, which is involved in the formation of P-glycoproteins (Pgps), but also elicited the downregulation and decomposition of mutant p53 in resistant cells to render cancer cells susceptible to chemodrugs [171]. The authors also loaded DOX inside the mesoporous shell of Au@SiO₂, and found that the resultant nanoplatform (termed Au@SiO₂-DOX) could avoid Pgp-mediated DOX efflux via the cellular internalization and lysosomal accumulation of Au@SiO₂-DOX. Moreover, under localized laser, Au@SiO₂-DOX enhanced the cancer cells’ sensitiveness to DOX due to the suppressed mutation of p53 (Figure 6(b)). Further, Du et al. employed cocktail chemotherapy, i.e., administration of two or more than two drugs, and low-temperature PTT at the same time to defeat cancer MDR [172]. They synthesized a dual drug-paired polyprodrug NP via the precipitation copolymerization of dopamine-DOX prodrug and subsequent cisplatin coordination. The NPs showed intracellular pH-responsive drug release and photothermal conversion capacity. Under mild hyperthermia, both the reversal of MDR and tumor eradication were achieved by the synergistic treatment.

To further decrease undesirable drug leakage and increase the drug release efficiency in targeted tumors, researchers have introduced some internal and external (as for mild PTT, it is generally NIR light irradiation) stimulus-responsive properties to the drug delivery systems. For example, low pH is a widely used stimulus for specific drug delivery. On the one hand, TME is weakly acidic mainly due to the abnormal metabolism and proton pump overexpression of tumor cells [111]. On the other hand, many NPs undergo the clathrin-dependent endocytosis to enter cells, which leads to the subsequent enzymatic degradation in the endosomes/lysosomes, where the pH is low [178]. In the past few years, some synergistic low-temperature PTT/chemotherapy nanoplatforms combining NIR light irradiation-triggerable and pH-responsive properties showed great capacity in controlling the delivery and release of drugs and achieved satisfactory cancer therapeutic effect [172–176]. For example, Lu et al. prepared copper sulfide-doped periodic mesoporous organosilica nanoparticles (CuS@PMOs) with excellent drug loading capacity and biodegradability [176]. Then, DOX was loaded into CuS@PMOs to obtain DOX-CuS@PMOs. The nanosystem could release DOX molecules upon the triggering of three stimuli—intracellular GSH, acidic environment in TME, and external mild laser irradiation. Besides, it was found that mild heat generated by CuS NPs exposed to the NIR laser could remarkably enhance the cellular uptake of DOX-CuS@PMOs, leading to the enhanced chemotherapeutic efficacy. In addition to the weakly acidic pH of TME, the overexpression of GSH in cancer cells can be also used to achieve stimuli-responsive drug release. Recently, a NP based on the DNA alkylating agent cisplatin was prepared by using an amphiphilic polymer containing a platinum(IV) (Pt(IV)) prodrug and pendant iodides [177]. On the one hand, the Pt(IV) on the main chain of the polymer could be reduced by GSH to obtain cisplatin and result in the breakage of the polymer. On the other hand, iodides on the side chains of the polymer depleted GSH via the iodo-thiol click chemistry, which circumvented the detoxification of cisplatin caused by GSH. Given that cisplatin is usually used in intraperitoneal hyperthermia perfusion therapy in clinical cancer treatment, the authors further introduced a PTA, IR780, into this platform. The obtained Pt-I-IR780 NPs under NIR light irradiation produced mild hyperthermia to promote GSH-mediated reduction of Pt(IV) and iodo-thiol click reaction (Figure 6(c)). Importantly, it was found that mild hyperthermia could facilitate cisplatin to form preferable interstrand crosslinks with DNA rather than intrastrand crosslinks. Since interstrand crosslinks are considerably more harmful to cancer cells than intrastrand crosslinks because of the difficulty of DNA interstrand repair, the Pt-I-IR780 NPs could realize enhanced cisplatin-mediated cancer chemotherapy (Figure 6(d)). This platform not only solves the problem of the unsatisfactory cisplatin toxicity to cancer cells but also achieves low-temperature PTT-enhanced chemotherapy. It is also believed that this work will pave the way for the further clinical translation of the combination of cisplatin-based chemotherapy and hyperthermia.

(2) RT. Radicals have strong redox activity and can lead to irreversible damage to some vital biomolecules like proteins, DNA/RNA, and lipids [179–181]. RT, which uses ionizing radiation (e.g., X-ray) to directly and/or indirectly react with organic molecules for generating toxic radicals to kill malignant cells, has become a key cancer therapeutic approach to elevate the cancer cells’ mortality and decrease unwanted side effects. In addition, employing RT to modulate DNA repair, cell cycle checkpoints, and related signal transduction pathways has also been considered as an encouraging tactic to affect the cellular fates [182]. In the past decades, there have been a large number of studies combining RT and PTT for elevating tumor elimination efficiency [183, 184]. The effect of RT may render cancer cells more sensitive to mild hyperthermia, so the association with RT provides the possibility of realizing low-temperature PTT. Actually, a host of researches have already demonstrated that the synergistic low-temperature PTT/RT has great potential in defeating cancers [185–189]. For example, Chen et al. fabricated an ¹³¹I-labeled and PEG-coated reduced GO (RGO) (¹³¹I-RGO-PEG) [186]. Under mild NIR light irradiation, the RGO with strong NIR absorption realized mild hyperthermia. Meanwhile, ¹³¹I-RGO-PEG exhibited high-energy X-ray emission capacity due to the radionuclide ¹³¹I, thus killing cancer cells through combined low-temperature PTT/RT. Besides utilizing radionuclides, some nanomaterials capable of converting light into heat and attenuating X-ray have also been exploited to fabricate nanoplatforms that show outstanding tumor eradication performance via synergistic low-temperature PTT/RT. For instance, Cheng et al. synthesized PEG-modified Gd³⁺-doped WS₂ (a typical type of two-dimensional transition metal dichalcogenides) nanoflakes with strong NIR absorption and X-ray attenuation capacity (Figure 7(a)) [187]. The nanoflakes could also be used as a competent contrast agent for X-ray computed tomography (CT), PA, and MR imaging. Similarly, Yu et al. prepared an all-in-one theranostic platform for synergistic mild PTT/RT and CT imaging [188]. The platform was composed of Bi NPs capped with thiols (via introducing 1-dodecanethiol) capable of protecting the NPs from oxidation and then modified with PEGylated phospholipids. In addition, inspired by the fact that mild hyperthermia is able to improve the tumor oxygenation through increasing the blood flow thus relieving the hypoxia-associated radioresistance, Song et al. constructed a Bi₂Se₃ hollow nanocube (HNC) (an NIR PTA) and then loaded GA into the its cavity and decorated the HNC with HA via redox-cleavable disulfide bonds to afford Bi₂Se₃ HNC-s-s-HA/GA [189]. The Bi₂Se₃ HNC-s-s-HA/GA could target CD44-overexpressing cancer cells, achieve GSH-sensitive GA release, and inhibit HSP90, and could hence accomplish more efficient low-temperature PTT under mild NIR laser irradiation. Moreover, both the X-ray attenuation capability of Bi₂Se₃ and the relief of hypoxia of TME due to mild PTT notably enhanced the efficacy of RT. It is noteworthy that under X-ray irradiation, Bi₂Se₃ HNCs could realize enhanced RT for eradicating tumor cells without the restriction of depth. Collectively, the above investigations demonstrate that RT represents a robust modality to enhance the efficiency of mild PTT to combat cancer.

(3) PDT. PDT is a treatment strategy that makes use of ROS generated by photosensitizers (PSs) exposed to certain light irradiation to cause lethal damage to cancer cells and tissues. Similar to PTT, PDT has an outstanding advantage of spatiotemporally-controlled selectivity and noninvasiveness. Nevertheless, PDT has been confronted with the obstacle that the administration of a high dose of PSs and the use of a strong laser may lead to unexpected phototoxicity to healthy tissues and unsatisfactory cure efficiency. Thanks to the development of nanotechnology, PDT can be facilely combined with PTT by designing desirable nanoplatforms which can potentiate the therapeutic efficacies via a synergistic effect [190–192]. On the one hand, mild heat can remarkably facilitate blood flow and supply sufficient oxygen for potentiating the efficacy of PDT [193, 194]. On the other hand, PDT can elevate the thermal sensitivity of cancer cells [194, 195]. In this way, mild laser irradiation can be adopted in PTT to achieve satisfactory anticancer performance with the assistance of PDT. In the past few years, the synchronous implementation of mild hyperthermia induced by NIR light irradiation and PDT has attracted increasing interest and exhibited remarkable credibility [196–200]. For instance, Liu et al. loaded a photodynamic agent chlorin e6 (Ce6) onto PEGylated MoS₂ nanosheets (in which MoS₂ nanosheets served as a PTA) for synergistic PDT/mild PTT [196]. In another example, our group used a protein-templated reaction to fabricate a BSA-stabilized, carbon dot-mediated, and Cu/Gd-doped nanodot (termed BCCG), which could serve as an eminent PTA [197]. We first synthesized CDs through the hydrothermal treatment of L-cysteine and o-phenylenediamine and then added these CDs into the pre-prepared BSA-Cu²⁺-Gd³⁺ complexes (Figure 7(b)). After covalently conjugating 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-α (HPPH), a PS, onto the surface of BCCG, the obtained nanoagents (termed BCCGH) showed excellent photothermal/photodynamic and fluorescence (FL)/magnetic properties to achieve FL/PA/MR/photothermal imaging-guided cancer therapy (Figure 7(b)). Due to their ultrasmall size and negatively charged surface, BCCGH had an advantage in enhanced tumor accumulation. Meanwhile, the ultrasmall size endowed the nanoagents with decreased systemic toxicity via their rapid renal excretion and increased therapeutic efficacy via deep tumor penetration. Moreover, the nanoagents could escape from lysosomes/endosomes and were mainly distributed in the large-volume organelle (endoplasmic reticulum) around the nucleus (Figure 7(c)). After mild laser irradiation, BCCGH showed significantly increased cellular uptake and exhibited nucleus-targeting capacity, thus greatly improving the anticancer therapeutic effect of PDT (Figure 7(d)). Finally, the nanoagents were found to be able to significantly eradicate tumors and thoroughly restrain the possible tumor recurrence. This work verifies that the combination of low-temperature PTT and PDT provides a promising strategy for cancer treatments.

Besides, by choosing the PSs that have overlapping absorption spectra with the PTAs and considering other issues such as the construction rationality of the combinational PTA/PS nanoplatforms, several studies successfully accomplished the combination of low-temperature PTT and PDT under a single laser, and in the meantime obtained other favorable characteristics, such as the multimodal imaging capacity [194, 198, 199], the specific nucleolus accumulation feature [198], and intrinsic GSH-responsive biodegradability [199]. For example, Zhang et al. reported a multifunctional zirconium-ferriporphyrin metal-organic framework (Zr-FeP MOF) nanoshuttle which not only acted as a PTA but also served as a catalyst for converting H₂O₂ and O₂ into ⋅OH and ¹O₂ for PDT [194]. After being modified with PEG, the nanoshuttle was further loaded with the HSP70 siRNA, an inhibitor of HSP70, to afford the final product termed siRNA/Zr-FeP MOF for mild hyperthermia (Figure 7(e)). Under NIR light irradiation, this nanoplatform demonstrated excellent tumor growth suppression effect via trimodal (photothermal/PA/CT) imaging-guided synergistic low-temperature PTT/PDT. Likewise, Wu et al. fabricated 17-AAG-encapustaed hollow mesoporous organosilica nanoparticles (HMONs), which were capped with BSAiridium oxide (IrO₂) NPs and conjugated with PEG to obtain 17-AAG@HMONs-BSA-IrO₂-PEG (AHBIP) for mild PTT and PDT [199]. The AHBIP showed the catalytic activity of converting H₂O₂ into O₂ attributed to BSA-IrO₂ NPs, which endowed this nanoplatform with two advantages—(1) the remission of tumor hypoxia, thus enhancing the efficacy of PDT, and (2) the reduction of the inflammatory cytokines induced by H₂O₂, thus alleviating excessive inflammation. In another example, Li et al. chose IR820 (a cyanine dye) to serve as both an NIR PTA and a PS to formulate a novel IR820/DTX-coloaded nanoplatform based on methoxy PEG-PCL (mPEG-PCL) micelle, and positively-charged PCL-grafted poly(ethylene imine) (PCL-g-PEI) which could stabilize the negatively charged IR820 via electrostatic interaction was introduced into the micelle [200]. It was found that the NIR absorption of IR820 was weakened due to the presence of PCL-g-PEI, which was beneficial for low-temperature PTT. Meanwhile, the ability of IR820 in producing singlet oxygen was scarcely influenced by PCL-g-PEI. Thus, this micellar nanosystem could simultaneously achieve mild PTT, efficient PDT, and DTX-mediated chemotherapy. Moreover, after further modification with a homing peptide, Lyp-1 (CGNKRTRGC), the resulting nanosystem displayed excellent antitumor performance. This work illustrates that, IR820, an agent that can simultaneously realize PTT and PDT, provides a choice for constructing novel nanoplatforms for achieving low-temperature PTT-involved synergistic cancer therapy.

(4) Sonodynamic Therapy, Pyroelectric Dynamic Therapy, and CDT. Apart from the traditional ROS generation methods, a number of strategies have been proposed to achieve ROS-mediated tumor eradication, which may render cancer cells more vulnerable to mild heat, thereby accomplishing low-temperature PTT. For instance, it is noteworthy that sonodynamic therapy (SDT) utilizing materials capable of producing ROS upon ultrasonication has paved a new way for cancer treatment [201]. For instance, Gong et al. found that the synthesis of titanium hydride (TiH_1.924) nanodots could be easily achieved by liquid-phase exfoliation treatment of TiH_1.924 powder in the presence of solvents with appropriate surface energy like dimethyl sulfoxide/N-methyl pyrrolidone (DMSO/NMP), DMSO, PEG 200, and NMP [202]. They chose NMP to fabricate TiH_1.924 nanodots because NMP offered outstanding exfoliation efficiency and the resultant nanodots exhibited uniform sizes and morphology. The nanodots served as an outstanding PTA and excellent sonosensitizer, which could achieve the combination of low-temperature PTT and SDT under NIR light irradiation and ultrasonication (Figure 8(a)). Besides SDT, Tang et al. fabricated a unique pyroelectric material, SnSe-polyvinylpyrrolidone (SnSe-PVP) nanorods, which converted the temperature fluctuations during the heating/cooling processes into electrical energy to react with water to obtain ROS [203]. They synthesized the SnSe nanorods by using a simple high-temperature thermal decomposition process and modified the surface of the obtained hydrophobic SnSe nanorods with PVP to enhance the hydrophilicity and biocompatibility. Under mild NIR-II light irradiation, SnSe-PVP not only realized high-performance photothermal conversion for low-temperature PTT but also accomplished pyroelectric dynamic therapy (PEDT). Moreover, in the past few years, CDT which utilizes metal ions (e.g., iron ions) to stimulate Fenton reaction capable of converting H₂O₂ into highly toxic ⋅OH to induce cancer cell death has been considered as an appreciated method to conquer cancers [116, 153, 204, 205]. Considering that elevation of temperature can enhance the Fenton reaction efficiency and ⋅OH productivity [206, 207], She et al. fabricated red blood cell (RBC) membrane-coated FeS₂ (FeS₂@RBCs) with strong absorption at the NIR-II window and Fenton reaction activity to realize the mild PTT-augmented CDT [208]. Similarly, Guo et al. constructed W₁₈O₄₉ nanorods for PAI-guided combined low-temperature PTT and CDT to treat cancer [209]. The authors utilized a one-step pyrolysis method to synthesize hydrophobic oleyl amine-coated W₁₈O₄₉ nanorods and then employed 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG₂₀₀₀) to prepare hydrophilic W₁₈O₄₉ nanorods via hydrophobic self-assembly. The finally obtained W₁₈O₄₉ nanorods showed both photothermal conversion and Fenton-like reaction capacities with satisfactory PAI contrast. The in vivo experiments demonstrated that the nanorods had outstanding potential for cancer treatment. These examples emphasize the feasibility of employing new ROS-generating cancer therapeutic strategies for achieving improved low-temperature PTT performance.

(5) Gas Therapy. Gas therapy utilizing gasotransmitters, which play an indispensable role in regulating diverse physiological behaviors, has been regarded as a “green” option of cancer treatment [210]. As for nitric oxide (NO), a high concentration of NO can directly lead to cell death by modulating various pathways, such as generating oxidative and nitrosative stresses, inhibiting DNA synthesis and repair, suppressing cellular respiration, and stimulating inflammatory reactions [211, 212]. Besides, it has been found that NO also displays advantages in enhancing the efficiency of other therapeutic modalities [213]. First, NO can sensitize the multidrug-resistant cells to chemodrugs. Second, NO is capable of acting as a radiosensitizer to assist RT in treating hypoxic tumors. Third, in the presence of ROS, NO can be oxidized into highly reactive peroxynitrite (ONOO⁻) to strengthen oxidative stress for killing cancer cells. Nevertheless, how to deliver exogenous gasotransmitters safely and precisely has become one of the most imperative questions in the gas therapy field. Hence, some recent state-of-the-art studies have focused on the design of various endogenous and/or exogenous stimulus-responsive NO-releasing nanostructures and their application in on-demand NO-sensitized synergistic cancer therapy [213]. Among them, the NIR light used in mild hyperthermia has been suggested to be an appropriate exogenous stimulus and the combination of low-temperature PTT and NO-mediated gas therapy has shown greatly improved cancer therapeutic effect. For example, Zhang et al. proposed that utilizing NO in mild PTT could improve the mild PTT’s capability of eradicating tumors [214]. They used Tween 20 (a commercial surfactant) to modify the surface of bismuth sulfide (Bi₂S₃) NPs to improve Bi₂S₃ NPs’ dispersity in physiological solutions and then added a hydrophobic NO donor, N,N

′

-di-sec-butyl-N,N

′

-dinitroso-1,4-phenylenediamine (BNN, which is relatively stable below 60°C) to form the final product BNN-Bi₂S₃ nanocomposites via hydrophobic interaction. Upon NIR light irradiation, the high local temperature on the surface of Bi₂S₃ NPs could cause on-demand NO release, and the surrounding temperature of the nanocomposites was kept at a low level to achieve mild PTT. Moreover, the released NO could suppress cancer cell autophagy-mediated self-repair which was triggered by mild PTT, and promote cancer cell apoptosis, thus rendering tumor vulnerable to mild heat (Figure 8(b)). Meanwhile, NO could diffuse homogeneously in the solid tumor to further enhance the effect of NO-sensitized low-temperature PTT for defeating cancer. Likewise, S-nitrosothiol, a thermosensitive donor of NO, was conjugated onto the core-shell structure of Au@SiO₂ nanomaterials (serving as PTAs) by You et al. [215]. Then, the authors decorated Au@SiO₂ with PEG, and loaded PES, an inhibitor of HSP70, into the cavity of the SiO₂ shell. Upon NIR light illumination, the NO produced by S-nitrosothiol and PES-mediated inhibition of HSP70 could collaboratively induce cell apoptosis or necrosis, thereby strengthening the cancer therapeutic effect of the synergistic low-temperature PTT/gas therapy.

(6) Gene Therapy. Given that nucleic acids are the determinant of almost all bioactivities from the molecular to physiological level, gene therapy delivering exogenous nucleic acids with the help of suitable vectors has gradually become one of the most prevalent cancer therapeutic strategies. As mentioned above, the major challenge in this field is designing delivery tools capable of releasing nucleic acids accurately and controllably as well as protecting them from degradation. It is suggested that PTT may provide an ideal way for nucleic acid delivery/release [109], because the heat induced by light can be employed as a trigger of nucleic acid release and can be spatiotemporally controlled. Besides, it has been found that the mild photothermal effect of PTAs can significantly facilitate the intracellular uptake of therapeutic nucleic acids and thus elevate the cancer treatment efficacy of gene therapy [109, 216]. In the past few years, some studies have suggested that the codelivery of PTAs and therapeutic nucleic acids encoded with HSP70 promoters provides the possibility of precisely regulating the expression of therapeutic genes under mild photothermal conditions [217–219]. The moderate increase of temperature caused by PTAs enables the heat shock factor (HSF) to transform from an inactive monomer to an active trimer, which is capable of translocating into the nucleus, and meanwhile, the therapeutic nucleic acids encoded with HSP70 promoters can enter the nucleus. Then, the intranuclear HSF trimer binds to the heat-shock element of the HSP70 promoter and activate the expression of the therapeutic genes cloned downstream of the HSP70 promoter. For example, Lyu et al. designed a dendronized semiconducting polymer (DSP) consisting of three components: the hydrophobic semiconducting backbone, the cationic third-generation polyamidoamine (PAMAM3) side chains, and the PEG segments, serving as the PTA, the gene vector, and the water-solubility enhancer, respectively [217]. After loading HSP-regulatable gene plasmids to DSPs, the authors obtained the nanocomplexes which achieved not only the efficient delivery of genes but also mild heat-controlled gene expression (Figure 8(c)). Similarly, Liu et al. selected PB and therapeutic plasmid DNA consisting of HSP70 promoter, tumor suppressor p53 gene, and green fluorescent protein (GFP) gene (acting as a reporter gene) to achieve thermocontrolled synergistic gene therapy/PTT [218]. It was observed that mild NIR light irradiation (temperature: ~41°C) could stimulate the HSP70 promoter for activating tumor suppressor p53-dependent apoptosis, and meanwhile, strong NIR light irradiation (temperature: ~50°C) resulted in the photothermal ablation of tumors through cellular dysregulation and necrosis. This work emphasizes the feasibility of combining low-temperature PTT-assisted gene therapy and conventional PTT to achieve effective tumor eradication by both apoptosis and necrosis.

Moreover, considering that oncolytic adenovirus (Ad) is widely recognized as a promising candidate for cancer gene therapy, and some studies demonstrate that mild hyperthermia can improve the anticancer effect of oncolytic Ads in vitro [220–222], Jung et al. fabricated an AuNR-mediated mild hyperthermia nanoplatform for enhanced oncolytic Ad gene delivery [223]. They combined the oncolytic Ad expressing VEGF promoter-targeted artificial transcriptional repressor zinc-finger protein with AuNR-mediated mild PTT. Under NIR laser irradiation, the mild heat generated by AuNRs notably promoted the endocytosis of oncolytic Ads, transgene expression, viral replication, and subsequent cytolysis of head and neck cancer cells, thus realizing the elevated efficiency of oncolytic Ads in cancer treatment.

Besides HSPs, Bcl2-associated athanogene domain 3 (BAG3) is also responsible for protecting cells from thermal attacks and developing cellular thermoresistance [224]. Inspired by this fact, Wang et al. used AuNRs to deliver BAG3-targeting siRNA oligomers to silence the expression of BAG3, thus rendering cancer cells vulnerable to low-temperature PTT [225]. The AuNRs were prepared by a seed-mediated growth method with hexadecyltrimethylammonium bromide and were sequentially modified with negatively charged poly(sodium 4-styrenesulfonate) and positively-charged poly(diallyldimethylammonium chloride) to form positive charged nanorods for connecting with BAG3-targeting siRNA oligomers through electrostatic interaction. The experimental results demonstrated that the resultant nanocomplexes exhibited great NIR photothermal conversion ability and the cancer cells were more sensitive to heat with the help of BAG3-targeting siRNA oligomers, thus realizing both gene delivery and low-temperature PTT.

(7) Immunotherapy. In the past few decades, immunotherapy has played an unparalleled role in defeating cancers and exhibited satisfactory capability to eradicate both primary and distant tumors [226, 227]. Since the immune system is a critical regulator of the tumor physiology and biology, which may result in the stimulation or suppression of tumor development, growth, invasion, and metastasis, it is important to develop effective immunotherapeutic strategies with the capacity to drive the immune system to pose a lethal threat to tumors rather than help them survive [228–231]. There have been numerous studies which focus on the exploration of cancer immune escape mechanisms and try to elevate the efficiency of immunotherapy [231]. Three major mechanisms have been proposed [231]: (1) the loss of antigenicity which has the potential to induce tumor-specific immune responses, (2) the poor immunogenicity of cancers, which may endow tumors with additional immunosuppressive properties via the overexpression of immune checkpoints and the secretion of suppressive cytokines, etc., and (3) the generation of immunosuppressive TME where the tumor-infiltrating lymphocytes (TILs) like macrophages do not attack cancer cells. In view of these problems, various immunotherapeutic approaches represented by chimeric antigen receptor (CAR) T cell therapy, immune checkpoint blockade (ICB), and cancer vaccines have been proposed and exhibited outstanding treatment performance [232–236]. Nevertheless, due to the heterogeneity and complexity of cancer, immunotherapy may not be able to activate the immune system to prevent tumor reoccurrence and metastasis, and its efficiency may be restrained by the dense extracellular matrix (ECM) and elevated interstitial fluid pressure (IFP) nearby the tumor tissue during the delivery of therapeutic molecules or cells [231, 237, 238]. Fortunately, the collaboration with low-temperature PTT can shed new light on the elevation of the immunotherapeutic efficiency. It has been found that mild hyperthermia can not only directly kill cancer cells but also lead to the partial disruption of ECM, the decrease of IFP, and the increase of the blood perfusion, which is beneficial for the delivery of immunotherapeutic agents and the recruitment and infiltration of lymphocytes. More importantly, mild hyperthermia can produce a favorable TME for immune responses via making dying cancer cells release tumor-associated antigens (TAAs) and damage-associated molecular pattern molecules (DAMPs) to modulate the immune system, consequently promoting the maturation of antigen-presenting cells (APCs), facilitating the secretion of immunostimulatory cytokines, and activating the cytotoxic lymphocytes to defeat tumors [167, 239–242]. In addition, Deng et al. found that the GO-mediated low-temperature PTT could inhibit the M2 polarization of tumor-associated macrophages (TAMs) (M2 phenotype TAMs are beneficial for tumor growth and metastasis) and thus contribute to evoking the immune system [243]. However, the immune responses induced by mild hyperthermia alone are usually not enough to remarkably reverse the tumor-mediated immunosuppressive microenvironment [244]. Therefore, on the one hand, the combination of low-temperature PTT and immunotherapy may pave a promising way for significantly evoking immune systems to eradicate cancers. On the other hand, the synergistic cancer treatment provides the possibility to achieve low-temperature PTT. For example, Chen et al. fabricated poly(lactic-co-glycolic acid) (PLGA)-ICG NPs to generate mild heat under NIR light irradiation and found that the mild heat could trigger increased infiltration and accumulation of the chondroitin sulfate proteoglycan-4- (CSPG4-) specific CAR T cells in tumor tissues [242]. This platform shows the eminent performance of mild PTT in elevating the therapeutic efficacy of CAR T cells in solid tumors.

In addition, ICB with the aim of inhibiting the immune checkpoints to activate immune responses has been widely exploited for the eradication of various cancers. It has been recognized that the two major determinants of the cancer therapeutic effect of ICB-based strategies are the expression of programmed death-ligand 1 (PD-L1) in the tumor tissues and the number of TILs [245–247]. However, a number of studies have demonstrated that some kinds of tumors were not vulnerable to ICB treatments because there are few TILs and low PD-L1 content in these tumor tissues [248–251]. Fortunately, due to its excellent potential for facilitating the recruitment of TILs and its capacity of inducing the elevated expression of PD-L1 on the plasma membranes of cancer cells, mild PTT is able to provide a possibility of remodeling the TME and enhancing the efficacy of ICB-based immunotherapy [239, 251–255]. For instance, Huang et al. encapsulated both IR820 and PD-L1 antibody (aPD-L1), which is capable of interfering with the interaction of programmed death protein 1 (PD-1) with PD-L1, into an injectable lipid gel (LG) depot which could undergo thermally reversible gel-to-sol phase transition [256]. Under the mild heat induced by the NIR light irradiation, the drug-loaded LG depot in sol phase successfully released aPD-L1 for achieving the symbiotic mild photothermal-assisted immunotherapy (SMPAI). This platform shows strong capacity in reversing the immunosuppressive microenvironment via ICB and exhibiting noticeable primary and distal tumor ablation effect (Figure 9(a)). It is noteworthy that the characteristics of this platform such as a consistent retention time in different tumors, the drug exposure dose, and the drug release amount and schedule could be precisely controlled through adjusting the component proportion of LG, changing drug loading amount, and manipulating NIR irradiation, which endowed the platform with great potential for personalized cancer therapy. Recently, Guo et al. designed a “one-for-all” nanosystem based on PEGylated PEI-coated monoelemental bismuthene loaded with siRNA against PD-L1 for mild photothermal immunotherapy [257]. This nanosystem could detach PEG in acidic TME, which resulted in the decreased size and formation of positively charged surface (due to the exposure of PEI) of these NPs, thus enhancing cancer cell uptake. After the endocytosis of the NPs, PEI assisted the NPs to escape from endosomes via the “proton sponge” effect, and meanwhile, the bismuthene-mediated mild hyperthermia could also promote the endosomal escape and induce the controllable release of siRNA against PD-L1. Then, under NIR light irradiation, the bismuthene released to the cytoplasm achieved low-temperature PTT, and it was found that mild hyperthermia stimulated a systemic immune response, recruited abundant TILs, and upregulated the expression of PD-L1 on tumor cells. The above two examples highlight the synergistic effect of low-temperature PTT and ICB-based immunotherapy and provide implications for the design of well-integrated nanoplatforms for cancer therapy.

In addition, cancer vaccines are designed to elicit long-lasting immune activation [258]. However, some studies have demonstrated that most cancer vaccines composed of defined peptide/protein antigens rather than all antigens which are obtained from whole tumor cells have the inferior ability of inducing immunological memory cells to develop an anticancer immunologic memory [259, 260]. Additionally, it is very difficult to collect the whole tumor to prepare a standardized vaccine line consisting of a variety of antigens from whole cancer cells. More importantly, TAAs may vary among tumors and individuals, which further restrains the development of cancer vaccines [261]. With regard to these problems, Chen et al. chose an immunomodulator resiquimod (R848) rather than antigens to develop a low-temperature PTT-mediated cancer vaccine [262]. R848 is the agonist of Toll-like receptors 7 and 8 (TLR-7/8) which are abundant in the immune cells that infiltrate TME, and it has been proved that the stimulation of TLR-7/8 by R848 can activate APCs via facilitating the maturation of DCs and subsequently transforming DCs’ phenotype from immunosuppressive to immunogenic [263–265]. Then, with the assistance of diverse proinflammatory cytokines (e.g., interleukin 6 and tumor necrosis factor-α) secreted by matured DCs, the antitumor immune responses can be activated. The authors used an amphiphilic copolymer consisting of hydrophobic polyaniline (PANI) and the hydrophilic glycol-chitosan (GCS) backbone to deliver R848 via loading R848 in the hydrophobic core [262]. PANI served as an NIR PTA and achieved low-temperature PTT, and mild hyperthermia showed satisfactory performance in rendering the primary tumor residues more sensitive to immunotherapy. Meanwhile, this platform successfully realized the development of robust and long-term immunological memory against cancer and the effective inhibition of tumor reoccurrence and metastasis. This work verifies that mild PTT can potentiate the immunotherapeutic efficiency of cancer vaccines.

Moreover, immunogenic cell death (ICD), a cell death type that can release DAMPs to activate the immune system to fight against tumors and establish long-term immunosurveillance, is gaining increasing research interest in cancer therapy [266]. It has been found that chemotherapy, PTT, RT, and PDT are all able to induce ICD and then stimulate the tumor-specific immune responses [267–269]. During ICD, calreticulin (a significant marker of ICD) can migrate from the endoplasmic reticulum of tumor cells to the plasma membrane and induce dendritic cells to engulf dying tumor cells and their debris. However, the undesirable toxicity to immune cells in harsh treatment conditions may severely affect the process of ICD and the reduced toxicity to cancer cells in mild treatment conditions can decrease the tumor therapeutic efficacy [270, 271]. Meanwhile, overheating can destroy antigens from dying tumor cells leading to the decreased tumor-killing immune responses [272]. Thus, the development of efficacious cancer therapeutic strategies with relatively mild treatment conditions is highly needed. Recently, the combination of low-temperature PTT and ICD-mediated immunotherapy has demonstrated its remarkable capacity of elevating the efficacy of cancer treatments [43, 272, 273]. For example, a triple therapeutic protocol combining low X-ray dose RT, low-temperature PTT, and immunotherapy was developed based on semiconductor heterojunction structured WO_2.9-WSe₂-PEG NPs [272]. Under X-ray irradiation, the NPs could catalyze H₂O₂ existing in TME to generate nonoxygen-dependent ROS which not only damaged cancer cells but also further triggered ICD. Besides, the NPs exhibited excellent NIR photothermal conversion capacity and it has been found that mild PTT was capable of triggering ICD to some extent. With the administration of aPD-L1, this platform effectively achieved tumor eradication and metastasis inhibition under mild temperature (induced by WO_2.9-WSe₂-PEG NPs upon mild NIR laser irradiation (0.5 W cm⁻²)) and low X-ray radiation dose. This work further verifies the ICD-inducing ability of RT and mild PTT and provides a valuable strategy for defeating cancer in a much safer condition. Additionally, Li et al. found that fever-type (i.e., low-temperature) PTT could facilitate the ROS-induced ICD to enhance immunotherapy [43]. They prepared an NIR PTA composed of Cu-containing layered double hydroxide (Cu-LDH), anchored highly reactive FeOOH nanodots which can generate ROS via Fenton reaction onto Cu-LDH, and inserted STA-9090 (an HSP90 inhibitor) into the gaps between the layers of Cu-LDH to promote cancer cell apoptosis at low temperatures, finally obtaining the FeOOH@STA/Cu-LDH nanohybrid. Under NIR light irradiation, the Fenton reaction-induced ICD was sequentially enhanced by mild hyperthermia and HSP90 inhibition and the primary and distant tumors were effectively eliminated by this synergistic therapeutic platform (Figure 9(b)). This work proposes a novel method for strengthening ICD-mediated immunotherapy via the synergistic Fenton reaction/low-temperature PTT. Moreover, the employment of an ICD inducer with mild PTT also shows eminent performance in eradicating tumors. Zhou et al. prepared a porous cobalt sulfide nanomaterial (PCS) via a simple DNA-templated hydrothermal method for PTT and the delivery of EGCG, an HSP70 inhibitor, and oxaliplatin, an ICD inducer [273]. The authors utilized the EGCG-mediated low-temperature PTT as the “first-hit” to kill tumors and the oxaliplatin-mediated ICD as the “second-hit” to eliminate the potential threat of tumor reoccurrence. Moreover, the release of EGCG and oxaliplatin was induced by pH- and heat-trigger, respectively, which realized the controllable drug delivery sequence. This work may inspire more researchers to employ low-temperature PTT to activate the immune system and amplify the cancer elimination effect of immunotherapy.

3. Conclusions and Perspectives

Less

In the past few years, low-temperature PTT based on nanomaterials has attracted considerable attention and exhibited promising potential in conquering some important problems in the biomedical region. It has been demonstrated that, with the assistance of nanotechnology, mild hyperthermia induced by NIR laser shows many advantages in elevating the therapeutic efficacy in diverse applications, because the well-designed nanoplatforms containing PTAs can (1) passively penetrate biofilms due to their nanoscale sizes and physicochemical properties or accumulate in the tumor tissues via EPR effect and specifically target bacteria or cancer cells via some integrated bacterium/tumor-targeting molecules or motifs, (2) possess some beneficial characteristics including stimulus-responsive property, organelle-targeting capability, and multimodal imaging capacity, (3) be combined with other therapeutic modalities to achieve synergistic therapies, and (4), as for cancer treatments, achieve significantly increased cellular uptake and tumor accumulation of the administrated therapeutics with the help of mild heat to potentiate the tumor therapeutic effect.

In this review, we have summarized the recent progress of nanomaterial-mediated low-temperature PTT from three aspects—(1) bacterial elimination, (2) wound treatment, and (3) cancer treatment. As for the antibiosis, there are two major obstacles impeding us to develop more effective strategies to avoid bacterial infection. On the one hand, due to the inappropriate utilization of diverse antibiotics, an increasing number of bacteria have become antibiotic-resistant and the antibacterial efficiency of antibiotics has been decreased dramatically. On the other hand, the troublesome biofilms largely hinder the interaction of antibacterial drugs and/or nanoagents with bacteria. Fortunately, it has been noted that mild PTT may render bacteria more susceptible to other treatments, and some novel methods based on low-temperature PTT have been proposed to solve these problems, including the synergistic NO-enhanced PDT/low-temperature PTT and QCS-MoS₂ nanoflake-mediated mild PTT for realizing bacterial resensitization to antibiotics [59, 60] as illustrated above. In regard to wound healing, it is inspiring that the combination of low-temperature PTT and other wound therapeutic strategies can achieve rapid and long-term wound healing [65–68]. It has been shown that, in the presence of some tissue regeneration-stimulating substances like bioactive ions, mild PTT can not only defeat bacterial infection but also alleviate excessive inflammation and facilitate the angiogenesis, which are crucial for wound healing [65, 66]. Besides, the introduction of “hot spring” effect also provides an encouraging method for treating chronic wounds [67]. To be noted, as being combined with MSC-based therapy, mild hyperthermia mediated by CuS@BSA NPs can enhance the differentiation of MSCs to form fibroblasts for promoting wound healing [68]. In view of cancer therapy, we first summarized the up-to-date strategies for realizing low-temperature PTT for tumor eradication. First, given that HSPs are the major determinant of the generation of thermal resistance and they play an important role in helping cancer cells escape from apoptosis-mediated death, the inhibition of HSPs using small-molecule HSP inhibitors (e.g., GA, Qu, 17-AAG, VER-155008, PES, EGCG, and BIIB021) and siRNAs can not only render tumors more vulnerable to mild heat for achieving low-temperature PTT but also promote the apoptosis-mediated cell death, which may further enhance the cancer treatment effect of mild PTT. Moreover, because both the synthesis of HSPs and the realization of HSP biological functions need energy, cancer starvation therapy which blocks/reduces the nutrient supply and/or exhausts the nutrients can lead to the decreased production of energy, thus inhibiting HSPs to accomplish low-temperature PTT. Second, the combination with autophagy-mediated cancer therapy sheds new light on the therapeutic effect enhancement of mild PTT. It has been found that the regulation of autophagy can contribute to low-temperature PTT for more effective tumor eradication. Third, the combination of organelle-targeting strategy with low-temperature PTT has also been exploited to achieve satisfactory cancer cell-killing effect because many organelles are vulnerable to mild hyperthermia and each organelle plays an indispensable role in maintaining intracellular homeostasis. Fourth, we concluded the synergistic therapy strategies that combine low-temperature PTT with other treatment modalities (e.g., chemotherapy, RT, gene therapy, and immune therapy). On the one hand, mild hyperthermia can markedly promote the tumor accumulation and retention of NPs/drugs via increasing blood flow and changing the compact tumor ECM into a loose one, thus elevating the intratumoral delivery of chemodrugs, radiosensitizers, nucleic acids, immunotherapeutic agents, etc. to achieve better cancer therapeutic outcomes. On the other hand, other treatments can render cancer cells more susceptible to mild hyperthermia, thus realizing low-temperature PTT. Additionally, it has also been verified that mild heat can alleviate the hypoxia of tumor tissues, which paves a promising way for potentiating the effect of oxygen-dependent treatments such as PDT and SDT. Furthermore, mild hyperthermia has the potential for modulating immune systems, i.e., activating the immunosuppressive microenvironment to form the immunostimulatory one [167, 239–243]. Therefore, the combination of low-temperature PTT and immunotherapy can significantly induce the immune responses to attack cancer cells and inhibit the metastasis and reoccurrence of tumors. More importantly, it is noteworthy that nanotechnology plays an unparalleled role in achieving synergistic therapy. By utilizing different synthesis and modification methods, various materials and agents possessing diverse therapeutic effects can be integrated into the nanoplatforms. Besides, the agents in nanosystems usually exhibit increased therapeutic effects and decreased side effects due to the strong drug-loading capacity, exogenous and/or endogenous stimulus-responsive property, and tumor targeting/accumulation ability of the nanocarriers.

Despite the above strategies developed, there are some problems which we must solve. First, although a large number of nanocarriers for low-temperature PTT have been developed and exhibited satisfactory characteristics like the increased drug encapsulation/loading capacity, decreased toxicity to normal cells, and good biocompatibility and biosafety, we still need to develop nanocarriers with stronger drug delivery capability, more desirable biodegradability, and enhanced stability in long-term blood circulation. Second, more strategies that can achieve low-temperature PTT need to be developed. For example, we can design more nanoplatforms for targeting other organelles except the nucleus, mitochondrion, and cytoskeleton and compare the effectiveness of the different strategies to optimize the organelle-targeted low-temperature PTT. Third, there are some novel and promising therapeutic modalities, including ferroptosis, ion-interference therapy, and electrodynamic therapy, which can also be adopted to be combined with low-temperature PTT for realizing satisfactory synergistic therapies. More importantly, although there have been studies focusing on the working mechanisms of the combination of low-temperature PTT and other treatments, we are supposed to figure out the more detailed action mechanisms of these synergistic therapies to propose more effective combinational strategies and more appropriate administration sequences. Likewise, to elevate the effectiveness of using mild PTT to treat bacterial infections and wounds, researchers are suggested to pay more attention to understanding and utilizing the complex mechanisms from various aspects like the behaviors and roles of bacteria or other indispensable types of cells in bacterial invasion and wound development. Moreover, there are few reports about using low-temperature PTT for treating other diseases like neurological disorders, metabolic diseases, and cardiovascular diseases. Therefore, it is suggested that mild PTT can be applied in more biomedical fields in the future.

To summarize, low-temperature PTT is a robust strategy for eliminating bacteria and cancers. We sincerely hope that this review may inspire more researchers to devote their efforts to this fascinating field and achieve significant advances in mild PTT-involved preclinical and clinical researches.

Funding

Less

Ministry of Education of the People's Republic of China(GKE-KF202001)
National Natural Science Foundation of China(21673037)

References

Less

J. J.

, Cheng

Y. J.

, and Zhang

X. Z.

, “Recent advances in nanomaterials for enhanced photothermal therapy of tumors,” Nanoscale, vol. 10, no. 48, pp. 22657–22672, 2018

Ray

P. C.

, Khan

S. A.

, Singh

A. K.

, Senapati

, and Fan

, “Nanomaterials for targeted detection and photothermal killing of bacteria,” Chemical Society Reviews, vol. 41, no. 8, pp. 3193–3209, 2012

Makabenta

J. M. V.

, Nabawy

, Li

C. H.

, Schmidt-Malan

, Patel

, and Rotello

V. M.

, “Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections,” Nature Reviews Microbiology, vol. 19, no. 1, pp. 23–36, 2021

Davis

M. E.

, Chen

, and Shin

D. M.

, “Nanoparticle therapeutics: an emerging treatment modality for cancer,” Nature Reviews Drug Discovery, vol. 7, no. 9, pp. 771–782, 2008

S. H.

, Chang

, Ebong

, Bhadviya

B. B.

, Mazumder

, and Lu

, “Nanoscale memristor device as synapse in neuromorphic systems,” Nano Letters, vol. 10, no. 4, pp. 1297–1301, 2010

Danhier

, Ansorena

, Silva

J. M.

, Coco

, Le Breton

, and Préat

, “PLGA-based nanoparticles: an overview of biomedical applications,” Journal of Controlled Release, vol. 161, no. 2, pp. 505–522, 2012

Jaque

, Martínez Maestro

, del Rosal

, Haro-Gonzalez

, Benayas

, Plaza

J. L.

, Rodríguez

E. M.

, and Solé

J. G.

, “Nanoparticles for photothermal therapies,” Nanoscale, vol. 6, no. 16, pp. 9494–9530, 2014

Xie

, Fan

, An

, Choi

, Duo

, Ge

, Zhang

, Nie

, Xie

, Zheng

, Chen

, Zhang

, and Kim

J. S.

, “Emerging combination strategies with phototherapy in cancer nanomedicine,” Chemical Society Reviews, vol. 49, no. 22, pp. 8065–8087, 2020

Wang

, Wu

, Shen

, Wang

, Shen

, Webster

T. J.

, and Deng

, “Applications of inorganic nanomaterials in photothermal therapy based on combinational cancer treatment,” International Journal of Nanomedicine, vol. 15, pp. 1903–1914, 2020

Yao

, Zheng

, Yao

, Xu

, Akakuru

O. U.

, Chen

, Yang

, and Wu

, “Rational design of nanomedicine for photothermal-chemodynamic bimodal cancer therapy,” WIREs Nanomedicine and Nanotechnology, no. article e1682, 2020

Yang

, Yang

, Pang

, Vara

, and Xia

, “Gold nanomaterials at work in biomedicine,” Chemical Reviews, vol. 115, no. 19, pp. 10410–10488, 2015

Yang

, Zhou

, Su

, Zhang

, and Dong

C. M.

, “One-pot photoreduction to prepare NIR-absorbing plasmonic gold nanoparticles tethered by amphiphilic polypeptide copolymer for synergistic photothermal-chemotherapy,” Chinese Chemical Letters, vol. 30, no. 1, pp. 187–191, 2019

Liu

, Li

, Chen

, and Zheng

, “Palladium-based nanomaterials for cancer imaging and therapy,” Theranostics, vol. 10, no. 22, pp. 10057–10074, 2020

Gao

, Jiang

Y. W.

, Jia

H. R.

, Sun

, Guo

, Yu

X.-W.

, Liu

, and Wu

F.-G.

, “From perinuclear to intranuclear localization: a cell-penetrating peptide modification strategy to modulate cancer cell migration under mild laser irradiation and improve photothermal therapeutic performance,” Biomaterials, vol. 223, article 119443, 2019

Jiang

Y. W.

, Gao

, Hu

, Liu

J.-B.

, Guo

, Zhang

, Yu

X.-W.

, Wu

F.-G.

, and Lu

, “Palladium nanosheet-knotted injectable hydrogels formed via palladium−sulfur bonding for synergistic chemo-photothermal therapy,” Nanoscale, vol. 12, no. 1, pp. 210–219, 2020

Shen

, Wang

, Zheng

, Zhu

, Jiang

, Fu

, and Yang

, “Magnetic nanoparticle clusters for photothermal therapy with near-infrared irradiation,” Biomaterials, vol. 39, pp. 67–74, 2015

Hessel

C. M.

, Pattani

V. P.

, Rasch

, Panthani

M. G.

, Koo

, Tunnell

J. W.

, and Korgel

B. A.

, “Copper selenide nanocrystals for photothermal therapy,” Nano Letters, vol. 11, no. 6, pp. 2560–2566, 2011

Wang

H. Y.

, Hua

X. W.

, Wu

F. G.

, Li

, Liu

, Gu

, Wang

, and Chen

, “Synthesis of ultrastable copper sulfide nanoclusters via trapping the reaction intermediate: potential anticancer and antibacterial applications,” ACS Applied Materials & Interfaces, vol. 7, no. 13, pp. 7082–7092, 2015

Bao

Y. W.

, Hua

X. W.

, Li

Y. H.

, Jia

H. R.

, and Wu

F. G.

, “Hyperthemia-promoted cytosolic and nuclear delivery of copper/carbon quantum dot-crosslinked nanosheets: multimodal imaging-guided photothermal cancer therapy,” ACS Applied Materials & Interfaces, vol. 10, no. 2, pp. 1544–1555, 2018

Gong

, Yan

, Zhou

, Xie

, Wu

, and Gu

, “Two-dimensional transition metal dichalcogenide nanomaterials for combination cancer therapy,” Journal of Materials Chemistry B, vol. 5, no. 10, pp. 1873–1895, 2017

del Rosal

, Carrasco

, Ren

, Benayas

, Vetrone

, Sanz-Rodríguez

, Ma

, Juarranz

Á.

, and Jaque

, “Infrared-emitting QDs for thermal therapy with real-time subcutaneous temperature feedback,” Advanced Functional Materials, vol. 26, no. 33, pp. 6060–6068, 2016

Tao

, Ji

, Xu

, Islam

M. A.

, Li

, Chen

, Saw

P. E.

, Zhang

, Bharwani

, Guo

, Shi

, and Farokhzad

O. C.

, “Antimonene quantum dots: synthesis and application as near-infrared photothermal agents for effective cancer therapy,” Angewandte Chemie International Edition, vol. 56, no. 39, pp. 11896–11900, 2017

Jung

H. S.

, Verwilst

, Sharma

, Shin

, Sessler

J. L.

, and Kim

J. S.

, “Organic molecule-based photothermal agents: an expanding photothermal therapy universe,” Chemical Society Reviews, vol. 47, no. 7, pp. 2280–2297, 2018

Pan

G. Y.

, Jia

H. R.

, Zhu

Y. X.

, Wang

R. H.

, Wu

F. G.

, and Chen

, “Dual channel activatable cyanine dye for mitochondrial imaging and mitochondria-targeted cancer theranostics,” ACS Biomaterials Science & Engineering, vol. 3, no. 12, pp. 3596–3606, 2017

Pan

G. Y.

, Jia

H. R.

, Zhu

Y. X.

, Sun

, Cheng

X. T.

, and Wu

F. G.

, “Cyanine-containing polymeric nanoparticles with imaging/therapy-switchable capability for mitochondria-targeted cancer theranostics,” ACS Applied Nano Materials, vol. 1, no. 6, pp. 2885–2897, 2018

Pan

G. Y.

, Jia

H. R.

, Zhu

Y. X.

, and Wu

F. G.

, “Turning double hydrophilic into amphiphilic: IR825-conjugated polymeric nanomicelles for near-infrared fluorescence imaging-guided photothermal cancer therapy,” Nanoscale, vol. 10, no. 4, pp. 2115–2127, 2018

Gao

, Jiang

Y. W.

, Sun

, Guo

, Jia

H.‐. R.

, Yu

X.‐. W.

, Pan

G.‐. Y.

, and Wu

F.‐. G.

, “Molecular targeting-mediated mild-temperature photothermal therapy with a smart albumin-based nanodrug,” Small, vol. 15, no. 33, article 1900501, 2019

Chen

, Zhang

, Guo

, Zhu

Y.‐. X.

, Liu

, Chen

, and Wu

F.‐. G.

, “Smart supramolecular “Trojan horse”-inspired nanogels for realizing light-triggered nuclear drug influx in drug-resistant cancer cells,” Advanced Functional Materials, vol. 29, no. 13, article 1807772, 2019

Jia

H. R.

, Zhu

Y. X.

, Liu

, Pan

G.-Y.

, Gao

, Sun

, Zhang

, Jiang

Y.-W.

, and Wu

F.-G.

, “Construction of dually responsive nanotransformers with nanosphere–nanofiber–nanosphere transition for overcoming the size paradox of anticancer nanodrugs,” ACS Nano, vol. 13, no. 10, pp. 11781–11792, 2019

Zhu

Y. X.

, Jia

H. R.

, Gao

, Pan

G.-Y.

, Jiang

Y.-W.

, Li

, Zhou

, Li

, She

, Ulrich

N. W.

, Chen

, and Wu

F.-G.

, “Mitochondria-acting nanomicelles for destruction of cancer cells via excessive mitophagy/autophagy-driven lethal energy depletion and phototherapy,” Biomaterials, vol. 232, article 119668, 2020

Liu

, Jia

H. R.

, Zhu

Y. X.

, Gao

, Jiang

Y.-W.

, Cheng

, Xu

K.-F.

, Yu

X.-W.

, and Wu

F.-G.

, “Mitochondrion- and nucleus-acting polymeric nanoagents for chemo-photothermal combination therapy,” Science China Materials, vol. 63, no. 5, pp. 851–863, 2020

Gao

, Jiang

Y. W.

, Guo

, Jia

H.‐. R.

, Cheng

, Deng

, Yu

X.‐. W.

, Zhu

Y.‐. X.

, Guo

H.‐. Y.

, Sun

, Liu

, Zhao

, Yang

, Yu

Z.‐. W.

, Raya

F. M. S.

, Liang

, and Wu

F.‐. G.

, “Enzyme-mediated tumor starvation and phototherapy enhance mild-temperature photothermal therapy,” Advanced Functional Materials, vol. 30, no. 16, article 1909391, 2020

, Cheng

, Wang

, Peng

, and Liu

, “Conjugated polymers for photothermal therapy of cancer,” Polymer Chemistry, vol. 5, no. 5, pp. 1573–1580, 2014

Gao

, Jiang

Y. W.

, Jia

H. R.

, and Wu

F. G.

, “Near-infrared light-controllable on-demand antibiotics release using thermo-sensitive hydrogel-based drug reservoir for combating bacterial infection,” Biomaterials, vol. 188, pp. 83–95, 2019

Ran

H. H.

, Cheng

, Gao

, Sun

, Jiang

Y.-W.

, Zhang

, Jia

H.-R.

, Qiao

, and Wu

F.-G.

, “Colistin-loaded polydopamine nanospheres uniformly decorated with silver nanodots: a nanohybrid platform with improved antibacterial and antibiofilm performance,” ACS Applied Bio Materials, vol. 3, no. 4, pp. 2438–2448, 2020

Lin

, Duan

Q. Y.

, and Wu

F. G.

, “Conjugated polymer-based photothermal therapy for killing microorganisms,” ACS Applied Polymer Materials, vol. 2, no. 10, pp. 4331–4344, 2020

Robinson

J. T.

, Tabakman

S. M.

, Liang

, Wang

, Casalongue

H. S.

, Vinh

, and Dai

, “Ultrasmall reduced graphene oxide with high near-infrared absorbance for photothermal therapy,” Journal of the American Chemical Society, vol. 133, no. 17, pp. 6825–6831, 2011

Yang

, Hu

, Ma

, Ye

, Cheng

, Shi

, Li

, and Liu

, “Multimodal imaging guided photothermal therapy using functionalized graphene nanosheets anchored with magnetic nanoparticles,” Advanced Materials, vol. 24, no. 14, pp. 1868–1872, 2012

Liang

, Diao

, Wang

, Gong

, Liu

, Hong

, Shi

, Dai

, and Liu

, “Tumor metastasis inhibition by imaging-guided photothermal therapy with single-walled carbon nanotubes,” Advanced Materials, vol. 26, no. 32, pp. 5646–5652, 2014

Zhao

, Jing

, Liu

, Gao

, Chen

, Song

, Wang

, Fang

, Qin

, Yuan

, Dai

, Qiao

Z.-A.

, and Wu

, “Mesoporous carbon nanospheres as a multifunctional carrier for cancer theranostics,” Theranostics, vol. 8, no. 3, pp. 663–675, 2018

Sun

, Zhang

, Jia

H. R.

, Zhu

Y.‐. X.

, Guo

, Gao

, Li

Y.‐. H.

, and Wu

F.‐. G.

, “Water-dispersible candle soot-derived carbon nano-onion clusters for imaging-guided photothermal cancer therapy,” Small, vol. 15, no. 11, article 1804575, 2019

Orosz

, Echtenacher

, Falk

, Rüschoff

, Weber

, and Männel

D. N.

, “Enhancement of experimental metastasis by tumor necrosis factor,” Journal of Experimental Medicine, vol. 177, no. 5, pp. 1391–1398, 1993

, Hao

, Sun

, Gu

, and Xu

Z. P.

, “Engineering a therapy-induced “immunogenic cancer cell death” amplifier to boost systemic tumor elimination,” Advanced Functional Materials, vol. 30, no. 22, article 1909745, 2020

Frey

, Weiss

E. M.

, Rubner

, Wunderlich

, Ott

O. J.

, Sauer

, Fietkau

, and Gaipl

U. S.

, “Old and new facts about hyperthermia-induced modulations of the immune system,” International Journal of Hyperthermia, vol. 28, no. 6, pp. 528–542, 2012

Hildebrandt

, Wust

, Ahlers

, Dieing

, Sreenivasa

, Kerner

, Felix

, and Riess

, “The cellular and molecular basis of hyperthermia,” Critical Reviews in Oncology/Hematology, vol. 43, no. 1, pp. 33–56, 2002

ANSI American National Standard for Safe Use of Lasers, Z136.1-2014, Laser Institute of America, Orlando, FL, USA, 2014

Jolly

, and Morimoto

R. I.

, “Role of the heat shock response and molecular chaperones in oncogenesis and cell death,” Journal of the National Cancer Institute, vol. 92, no. 19, pp. 1564–1572, 2000

Verwaal

V. J.

, van Ruth

, de Bree

, van Slooten

G. W.

, van Tinteren

, Boot

, and Zoetmulder

F. A. N.

, “Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer,” Journal of Clinical Oncology, vol. 21, no. 20, pp. 3737–3743, 2003

Yan

T. D.

, Deraco

, Baratti

, Kusamura

, Elias

, Glehen

, Gilly

F. N.

, Levine

E. A.

, Shen

, Mohamed

, Moran

B. J.

, Morris

D. L.

, Chua

T. C.

, Piso

, and Sugarbaker

P. H.

, “Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience,” Journal of Clinical Oncology, vol. 27, no. 36, pp. 6237–6242, 2009

Shang

, Chan

S. Y.

, Song

, Li

, and Huang

, “The strategies of pathogen-oriented therapy on circumventing antimicrobial resistance,” Research, vol. 2020, article 2016201, –32, 2020

Xiu

, Gan

, Wen

, Qiu

, Dai

, Dong

, Li

, Yuwen

, Weng

, Teng

, and Mou

, “Biofilm microenvironment-responsive nanotheranostics for dual-mode imaging and hypoxia-relief-enhanced photodynamic therapy of bacterial infections,” Research, vol. 2020, article 9426453, –15, 2020

J. W.

, Yao

, and Xu

Z. K.

, “Nanomaterials with a photothermal effect for antibacterial activities: an overview,” Nanoscale, vol. 11, no. 18, pp. 8680–8691, 2019

Xin

, Shah

, Nawaz

, Xie

, Akram

M. Z.

, Batool

, Tian

, Jan

S. U.

, Boddula

, Guo

, Liu

, and Gong

J. R.

, “Antibacterial carbon-based nanomaterials,” Advanced Materials, vol. 31, no. 45, article 1804838, 2019

Xia

M. Y.

, Xie

, Yu

C. H.

, Chen

G.-Y.

, Li

Y.-H.

, Zhang

, and Peng

, “Graphene-based nanomaterials: the promising active agents for antibiotics-independent antibacterial applications,” Journal of Controlled Release, vol. 307, pp. 16–31, 2019

, Li

, Wang

, Ye

, Lei

, Jia

, Jin

, Ren

K.-F.

, and Ji

, “Surface-adaptive gold nanoparticles with effective adherence and enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus biofilm,” ACS Nano, vol. 11, no. 9, pp. 9330–9339, 2017

Nakal-Chidiac

, García

, García-Fernández

, Martín-Saavedra

F. M.

, Sánchez-Casanova

, Escudero-Duch

, Román

J. S.

, Vilaboa

, and Aguilar

M. R.

, “Chitosan-stabilized silver nanoclusters with luminescent, photothermal and antibacterial properties,” Carbohydrate Polymers, vol. 250, article 116973, 2020

Cheeseman

, Christofferson

A. J.

, Kariuki

, Christofferson

A. J.

, Kariuki

, Cozzolino

, Daeneke

, Crawford

R. J.

, Truong

V. K.

, Chapman

, and Elbourne

, “Antimicrobial metal nanomaterials: from passive to stimuli-activated applications,” Advanced Science, vol. 7, no. 10, article 1902913, 2020

Fan

X. L.

, Li

H. Y.

, Ye

W. Y.

, Zhao

M.-Q.

, Huang

D.-n.

, Fang

, Zhou

B.-Q.

, Ren

K.-F.

, Ji

, and Fu

G.-S.

, “Magainin-modified polydopamine nanoparticles for photothermal killing of bacteria at low temperature,” Colloids and Surfaces B: Biointerfaces, vol. 183, article 110423, 2019

Yuan

, Lin

, He

, Tao

, Chen

, Zhang

, Liu

, and Cai

, “Near-infrared light-triggered nitric-oxide-enhanced photodynamic therapy and low-temperature photothermal therapy for biofilm elimination,” ACS Nano, vol. 14, no. 3, pp. 3546–3562, 2020

Huang

, Gao

, Li

, Gao

, Han

, Jin

, Yao

, and Ji

, “Ofloxacin loaded MoS₂ nanoflakes for synergistic mild-temperature photothermal/antibiotic therapy with reduced drug resistance of bacteria,” Nano Research, vol. 13, no. 9, pp. 2340–2350, 2020

Tan

, Zhou

, Liu

, Li

, Zheng

, Cui

, Yang

, Liang

, Li

, Feng

, Zhu

, Yeung

K. W. K.

, Yang

, Wang

, and Wu

, “Overcoming multidrug-resistant MRSA using conventional aminoglycoside antibiotics,” Advanced Science, vol. 7, no. 9, article 1902070, 2020

Simões

, Miguel

S. P.

, Ribeiro

M. P.

, Coutinho

, Mendonça

A. G.

, and Correia

I. J.

, “Recent advances on antimicrobial wound dressing: a review,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 127, pp. 130–141, 2018

Saghazadeh

, Rinoldi

, Schot

, Kashaf

S. S.

, Sharifi

, Jalilian

, Nuutila

, Giatsidis

, Mostafalu

, Derakhshandeh

, Yue

, Swieszkowski

, Memic

, Tamayol

, and Khademhosseini

, “Drug delivery systems and materials for wound healing applications,” Advanced Drug Delivery Reviews, vol. 127, pp. 138–166, 2018

Wang

P. H.

, Huang

B. S.

, Horng

H. C.

, Yeh

C. C.

, and Chen

Y. J.

, “Wound healing,” Journal of the Chinese Medical Association, vol. 81, no. 2, pp. 94–101, 2018

, Liu

, Tan

, Cui

, Yang

, Zhu

, Li

, Yuan

, Zheng

, Yeung

K. W. K.

, Chu

P. K.

, and Wu

, “Controlled-temperature photothermal and oxidative bacteria killing and acceleration of wound healing by polydopamine-assisted Au-hydroxyapatite nanorods,” Acta Biomaterialia, vol. 77, pp. 352–364, 2018

, Xu

, Liu

, Li

, Han

, Zheng

, Chen

D.‐f.

, Yeung

K. W. K.

, Cui

, Li

, Liang

, Zhu

, Wang

, and Wu

, “Photoelectrons mediating angiogenesis and immunotherapy through heterojunction film for noninvasive disinfection,” Advanced Science, vol. 7, no. 17, article 2000023, 2020

Sheng

, Zhang

, Wang

, Ma

, Xu

, Ma

, Zhang

, Pei

, and Chang

, “A novel "hot spring"-mimetic hydrogel with excellent angiogenic properties for chronic wound healing,” Biomaterials, vol. 264, article 120414, 2021

Xiao

, Peng

, Liu

, Chen

, Shi

, Han

, Yang

, Zhong

, Zha

, Qu

, and Qian

, “Ultrasmall CuS@BSA nanoparticles with mild photothermal conversion synergistically induce MSCs-differentiated fibroblast and improve skin regeneration,” Theranostics, vol. 10, no. 4, pp. 1500–1513, 2020

Liang

, Kang

, Wang

, Yu

, Fan

, and Takashi

, “Carbonate ion-enriched hot spring water promotes skin wound healing in nude rats,” PLoS One, vol. 10, no. 2, article e0117106, 2015

Jiang

, Jahagirdar

B. N.

, Reinhardt

R. L.

, Schwartz

R. E.

, Keene

C. D.

, Ortiz-Gonzalez

X. R.

, Reyes

, Lenvik

, Lund

, Blackstad

, Du

, Aldrich

, Lisberg

, Low

W. C.

, Largaespada

D. A.

, and Verfaillie

C. M.

, “Pluripotency of mesenchymal stem cells derived from adult marrow,” Nature, vol. 418, no. 6893, pp. 41–49, 2002

Sharma

R. R.

, Pollock

, Hubel

, and McKenna

, “Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices,” Transfusion, vol. 54, no. 5, pp. 1418–1437, 2014

Dongre

, and Weinberg

R. A.

, “New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer,” Nature Reviews Molecular Cell Biology, vol. 20, no. 2, pp. 69–84, 2019

Markowicz

, Koellensperger

, Neuss

, Koenigschulte

, Bindler

, and Pallua

, “Human bone marrow mesenchymal stem cells seeded on modified collagen improved dermal regeneration in vivo,” Cell Transplantation, vol. 15, no. 8–9, pp. 723–732, 2006

Turski

M. L.

, and Thiele

D. J.

, “New roles for copper metabolism in cell proliferation, signaling, and disease,” Journal of Biological Chemistry, vol. 284, no. 2, pp. 717–721, 2009

Yang

S. J.

, Uriu-Adams

J. Y.

, Keen

C. L.

, Rucker

R. B.

, and Lanoue

, “Effects of copper deficiency on mouse yolk sac vasculature and expression of angiogenic mediators,” Birth Defects Research B: Developmental and Reproductive Toxicology, vol. 77, no. 5, pp. 445–454, 2006

Isaacs

J. S.

, Xu

, and Neckers

, “Heat shock protein 90 as a molecular target for cancer therapeutics,” Cancer Cell, vol. 3, no. 3, pp. 213–217, 2003

Daugaard

, Rohde

, and Jäättelä

, “The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions,” FEBS Letters, vol. 581, no. 19, pp. 3702–3710, 2007

Beere

H. M.

, Wolf

B. B.

, Cain

, Mosser

D. D.

, Mahboubi

, Kuwana

, Tailor

, Morimoto

R. I.

, Cohen

G. M.

, and Green

D. R.

, “Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome,” Nature Cell Biology, vol. 2, no. 8, pp. 469–475, 2000

Picard

, “Heat-shock protein 90, a chaperone for folding and regulation,” Cellular and Molecular Life Sciences, vol. 59, no. 10, pp. 1640–1648, 2002

Maloney

, and Workman

, “HSP90 as a new therapeutic target for cancer therapy: the story unfolds,” Expert Opinion on Biological Therapy, vol. 2, no. 1, pp. 3–24, 2002

Hong

D. S.

, Banerji

, Tavana

, George

G. C.

, Aaron

, and Kurzrock

, “Targeting the molecular chaperone heat shock protein 90 (HSP90): lessons learned and future directions,” Cancer Treatment Reviews, vol. 39, no. 4, pp. 375–387, 2013

Nylandsted

, Rohde

, Brand

, Bastholm

, Elling

, and Jäättelä

, “Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 14, pp. 7871–7876, 2000

Ravagnan

, Gurbuxani

, Susin

S. A.

, Maisse

, Daugas

, Zamzami

, Mak

, Jäättelä

, Penninger

J. M.

, Garrido

, and Kroemer

, “Heat-shock protein 70 antagonizes apoptosis-inducing factor,” Nature Cell Biology, vol. 3, no. 9, pp. 839–843, 2001

Nylandsted

, Gyrd-Hansen

, Danielewicz

, Fehrenbacher

, Lademann

, Høyer-Hansen

, Weber

, Multhoff

, Rohde

, and Jäättelä

, “Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization,” Journal of Experimental Medicine, vol. 200, no. 4, pp. 425–435, 2004

Trepel

, Mollapour

, Giaccone

, and Neckers

, “Targeting the dynamic HSP90 complex in cancer,” Nature Reviews Cancer, vol. 10, no. 8, pp. 537–549, 2010

Jego

, Hazoumé

, Seigneuric

, and Garrido

, “Targeting heat shock proteins in cancer,” Cancer Letters, vol. 332, no. 2, pp. 275–285, 2013

Murphy

M. E.

, “The HSP70 family and cancer,” Carcinogenesis, vol. 34, no. 6, pp. 1181–1188, 2013

Whitesell

, Mimnaugh

E. G.

, De Costa

, Myers

C. E.

, and Neckers

L. M.

, “Inhibition of heat shock protein HSP90-pp60^v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 18, pp. 8324–8328, 1994

Kamal

, Thao

, Sensintaffar

, Zhang

, Boehm

M. F.

, Fritz

L. C.

, and Burrows

F. J.

, “A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors,” Nature, vol. 425, no. 6956, pp. 407–410, 2003

Davenport

, Manjarrez

J. R.

, Peterson

, Krumm

, Blagg

B. S. J.

, and Matts

R. L.

, “Gambogic acid, a natural product inhibitor of Hsp90,” Journal of Natural Products, vol. 74, no. 5, pp. 1085–1092, 2011

Massey

A. J.

, Williamson

D. S.

, Browne

, Murray

J. B.

, Dokurno

, Shaw

, Macias

A. T.

, Daniels

, Geoffroy

, Dopson

, Lavan

, Matassova

, Francis

G. L.

, Graham

C. J.

, Parsons

, Wang

, Padfield

, Comer

, Drysdale

M. J.

, and Wood

, “A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells,” Cancer Chemotherapy and Pharmacology, vol. 66, no. 3, pp. 535–545, 2010

Matokanovic

, Barisic

, Filipovic-Grcic

, and Maysinger

, “Hsp70 silencing with siRNA in nanocarriers enhances cancer cell death induced by the inhibitor of Hsp90,” European Journal of Pharmaceutical Sciences, vol. 50, no. 1, pp. 149–158, 2013

Yang

, Zhu

, Dong

, Chao

, Xu

, Chen

, and Liu

, “1D coordination polymer nanofibers for low-temperature photothermal therapy,” Advanced Materials, vol. 29, no. 40, article 1703588, 2017

, Zhu

, Ma

, Yang

, Wang

, Wu

, Wang

, Chen

, Wang

, Liu

, and Yuan

, “Rapid synthesis of a Bi@ZIF-8 composite nanomaterial as a near-infrared-II (NIR-II) photothermal agent for the low-temperature photothermal therapy of hepatocellular carcinoma,” Nanoscale, vol. 12, no. 32, pp. 17064–17073, 2020

Sun

, Li

, Teng

, Wang

, Guo

, and Wang

, “NIR-controlled HSP90 inhibitor release from hollow mesoporous nanocarbon for synergistic tumor photothermal therapy guided by photoacoustic imaging,” Nanoscale, vol. 12, no. 27, pp. 14775–14787, 2020

Sun

, Chen

, Wang

, Liu

, and Xie

, “Enhanced efficacy of photothermal therapy by combining a semiconducting polymer with an inhibitor of a heat shock protein,” Materials Chemistry Frontiers, vol. 3, no. 1, pp. 127–136, 2019

Chen

B. Q.

, Kankala

R. K.

, Zhang

, Xiang

S.-T.

, Tang

H.-X.

, Wang

, Yang

D.-Y.

, Wang

S.-B.

, Zhang

Y. S.

, Liu

, and Chen

A.-Z.

, “Gambogic acid augments black phosphorus quantum dots (BPQDs)-based synergistic chemo-photothermal therapy through downregulating heat shock protein expression,” Chemical Engineering Journal, vol. 390, article 124312, 2020

Bai

, Yuan

, Cai

, Qiu

, Jin

, Liu

, Li

, and Chen

, “Stimuli-responsive scaffold for breast cancer treatment combining accurate photothermal therapy and adipose tissue regeneration,” Advanced Functional Materials, vol. 29, no. 36, article 1904401, 2019

Yang

G. G.

, Zhou

D. J.

, Pan

Z. Y.

, Yang

, Zhang

D.-Y.

, Cao

, Ji

L.-N.

, and Mao

Z.-W.

, “Multifunctional low-temperature photothermal nanodrug with in vivo clearance, ROS-scavenging and anti-inflammatory abilities,” Biomaterials, vol. 216, article 119280, 2019

100

Ali

M. R. K.

, Ali

H. R.

, Rankin

C. R.

, and El-Sayed

M. A.

, “Targeting heat shock protein 70 using gold nanorods enhances cancer cell apoptosis in low dose plasmonic photothermal therapy,” Biomaterials, vol. 102, pp. 1–8, 2016

101

Luo

, Wang

, Deng

, Yang

, Ke

, Yang

, He

, Guo

, Yu

, Wu

, and Chen

, “Mutually synergistic nanoparticles for effective thermo-molecularly targeted therapy,” Advanced Functional Materials, vol. 27, no. 39, article 1702834, 2017

102

Tang

, Tan

, Shi

, Peng

, Xiao

, Li

, Chen

, Yang

, and Qian

, “Gold nanorods together with HSP inhibitor-VER-155008 micelles for colon cancer mild-temperature photothermal therapy,” Acta Pharmaceutica Sinica B, vol. 8, no. 4, pp. 587–601, 2018

103

Liu

, Ma

, An

, Li

, Liu

, Wang

, Guo

, Wang

, and Zhou

, “Thermoresponsive nanogel-encapsulated PEDOT and HSP70 inhibitor for improving the depth of the photothermal therapeutic effect,” Advanced Functional Materials, vol. 26, no. 26, pp. 4749–4759, 2016

104

Jiang

, Liu

, Ma

, Mao

, Liu

, Zhai

, and Zhou

, “Biocompatible heat-shock protein inhibitor-delivered flowerlike short-wave infrared nanoprobe for mild temperature-driven highly efficient tumor ablation,” ACS Applied Materials & Interfaces, vol. 11, no. 7, pp. 6820–6828, 2019

105

Zhang

, Wu

, Akakuru

O. U.

, Yao

, Sun

, Chen

, Ren

, Wu

, and Huang

, “Hsp90 inhibitor-loaded IR780 micelles for mitochondria-targeted mild-temperature photothermal therapy in xenograft models of human breast cancer,” Cancer Letters, vol. 500, pp. 41–50, 2021

106

Wang

, Gao

, Liu

, Ma

, Liu

, Du

, and Zhou

, “Cypate-conjugated porous upconversion nanocomposites for programmed delivery of heat shock protein 70 small interfering RNA for gene silencing and photothermal ablation,” Advanced Functional Materials, vol. 26, no. 20, pp. 3480–3489, 2016

107

Wang

, Li

, Zhang

, Ma

, Liu

, Gao

, Zhang

, and Gu

, “Laser-triggered small interfering RNA releasing gold nanoshells against heat shock protein for sensitized photothermal therapy,” Advanced Science, vol. 4, no. 2, article 1600327, 2017

108

Ding

, Gao

, Huang

, Ge

, Xie

, Qian

, Song

, Li

, Zhu

, and Zhang

, “Polydopamine-coated nucleic acid nanogel for siRNA-mediated low-temperature photothermal therapy,” Biomaterials, vol. 245, article 119976, 2020

109

Kim

, Kim

, Jeong

, and Kim

W. J.

, “Synergistic nanomedicine by combined gene and photothermal therapy,” Advanced Drug Delivery Reviews, vol. 98, pp. 99–112, 2016

110

, Chen

, Zeng

, Chen

, and Gu

, “Advances in nanomedicine for cancer starvation therapy,” Theranostics, vol. 9, no. 26, pp. 8026–8047, 2019

111

El-Sawy

H. S.

, Al-Abd

A. M.

, Ahmed

T. A.

, El-Say

K. M.

, and Torchilin

V. P.

, “Stimuli-responsive nano-architecture drug-delivery systems to solid tumor micromilieu: past, present, and future perspectives,” ACS Nano, vol. 12, no. 11, pp. 10636–10664, 2018

112

Son

, Kim

, You

D. G.

, Yoon

H. Y.

, Yhee

J. Y.

, Kim

, Kwon

I. C.

, and Kim

S. H.

, “Antitumor therapeutic application of self-assembled RNAi-AuNP nanoconstructs: combination of VEGF-RNAi and photothermal ablation,” Theranostics, vol. 7, no. 1, pp. 9–22, 2017

113

Chen

W. H.

, Luo

G. F.

, Lei

, Hong

, Qiu

W.-X.

, Liu

L.-H.

, Cheng

S.-X.

, and Zhang

X.-Z.

, “Overcoming the heat endurance of tumor cells by interfering with the anaerobic glycolysis metabolism for improved photothermal therapy,” ACS Nano, vol. 11, no. 2, pp. 1419–1431, 2017

114

L. H.

, Qi

, Lin

, and Huang

, “Catalytic chemistry of glucose oxidase in cancer diagnosis and treatment,” Chemical Society Reviews, vol. 47, no. 17, pp. 6454–6472, 2018

115

L. H.

, Qi

, Hu

Y. R.

, Lin

, and Huang

, “Glucose oxidase-instructed multimodal synergistic cancer therapy,” Advanced Materials, vol. 31, no. 21, article 1808325, 2019

116

Guo

, Jia

H. R.

, Zhang

, Sun

, Wang

S.‐. Z.

, Zhao

, and Wu

F.‐. G.

, “A glucose/oxygen-exhausting nanoreactor for starvation- and hypoxia-activated sustainable and cascade chemo-chemodynamic therapy,” Small, vol. 16, no. 31, article 2000897, 2020

117

Cao

, Qian

, Luo

, Cheng

, Yang

, Wang

, Yuan

, Fan

, Li

, and Wang

, “A multimodal imaging-guided nanoreactor for cooperative combination of tumor starvation and multiple mechanism-enhanced mild temperature phototherapy,” Biomaterials Science, vol. 8, no. 23, pp. 6561–6578, 2020

118

Zhou

, Li

, Hou

, Luo

, Chen

, Cao

, Huo

, Xue

, Sutrisno

, Hao

, Cao

, Ran

, Lu

, Li

, and Cai

, “Engineering of a nanosized biocatalyst for combined tumor starvation and low-temperature photothermal therapy,” ACS Nano, vol. 12, no. 3, pp. 2858–2872, 2018

119

Tang

, Fan

, Zhang

, Yang

, Li

, Wang

, Chiang

Y.‐. L.

, Liu

, Deng

, He

, Shen

, Jacobson

, Aronova

M. A.

, Jin

, Xie

, and Chen

, “Wet/sono-chemical synthesis of enzymatic two-dimensional MnO₂ nanosheets for synergistic catalysis-enhanced phototheranostics,” Advanced Materials, vol. 31, no. 19, article 1900401, 2019

120

Dang

, Ye

, Li

, Liang

, Li

, and Yin

, “Multivalency-assisted membrane-penetrating siRNA delivery sensitizes photothermal ablation via inhibition of tumor glycolysis metabolism,” Biomaterials, vol. 223, article 119463, 2019

121

Mizushima

, “Autophagy: process and function,” Genes & Development, vol. 21, no. 22, pp. 2861–2873, 2007

122

Bhutia

S. K.

, Mukhopadhyay

, Sinha

, Das

D. N.

, Panda

P. K.

, Patra

S. K.

, Maiti

T. K.

, Mandal

, Dent

, Wang

X.-Y.

, Das

S. K.

, Sarkar

, and Fisher

P. B.

, “Autophagy: Cancer's Friend or Foe?,” Advances in Cancer Research, vol. 118, pp. 61–95, 2013

123

Levy

J. M. M.

, Towers

C. G.

, and Thorburn

, “Targeting autophagy in cancer,” Nature Reviews Cancer, vol. 17, no. 9, pp. 528–542, 2017

124

Yun

C. W.

, and Lee

S. H.

, “The roles of autophagy in cancer,” International Journal of Molecular Sciences, vol. 19, no. 11, article 3466, 2018

125

Amaravadi

R. K.

, Kimmelman

A. C.

, and Debnath

, “Targeting autophagy in cancer: recent advances and future directions,” Cancer Discovery, vol. 9, no. 9, pp. 1167–1181, 2019

126

Zhang

, Chen

, Guo

, Jia

H. R.

, Jiang

Y. W.

, and Wu

F. G.

, “Endosome/lysosome-detained supramolecular nanogels as an efflux retarder and autophagy inhibitor for repeated photodynamic therapy of multidrug-resistant cancer,” Nanoscale Horizons, vol. 5, no. 3, pp. 481–487, 2020

127

Lin

, Huang

, Wu

, Zhou

, Jin

, Wei

, Zhang

, Zheng

, Zhang

, Xu

, and Hu

, “Inhibition of autophagy enhances the anticancer activity of silver nanoparticles,” Autophagy, vol. 10, no. 11, pp. 2006–2020, 2014

128

Yang

, Ding

, Chen

, and Shi

, “Augmenting tumor-starvation therapy by cancer cell autophagy inhibition,” Advanced Science, vol. 7, no. 6, article 1902847, 2020

129

Zhou

, Yan

, Hu

, Zou

, Li

, Ma

, Zhang

, and Cheng

, “Autophagy inhibition enabled efficient photothermal therapy at a mild temperature,” Biomaterials, vol. 141, pp. 116–124, 2017

130

Wang

, Zhao

, Wang

, Hao

, Kong

, Zhao

, Gao

, Li

, Liu

, Yang

, Zhang

, and Jiang

, “Inhibition of autophagy promoted apoptosis and suppressed growth of hepatocellular carcinoma upon photothermal exposure,” Journal of Biomedical Nanotechnology, vol. 15, no. 4, pp. 813–821, 2019

131

Shao

, Li

, Huang

, Wang

, Lu

, Jia

, Pan

, Cui

, Ge

, Deng

, and Wu

, “Complementary autophagy inhibition and glucose metabolism with rattle-structured polydopamine@mesoporous silica nanoparticles for augmented low-temperature photothermal therapy and in vivo photoacoustic imaging,” Theranostics, vol. 10, no. 16, pp. 7273–7286, 2020

132

Wang

, Chen

, Lin

, Ying

, Huang

, Cai

, Xiao

, Zhang

, and Cheng

, “Breaking the vicious cycle between tumor cell proliferation and bone resorption by chloroquine-loaded and bone-targeted polydopamine nanoparticles,” Science China Materials, vol. 64, no. 2, pp. 474–487, 2021

133

Zhou

, Yan

, Wang

, Zhang

, and Cheng

, “Melanin-like nanoparticles decorated with an autophagy-inducing peptide for efficient targeted photothermal therapy,” Biomaterials, vol. 203, pp. 63–72, 2019

134

Guo

, Wei

, Chen

, Zhang

, Yang

, and Zhou

, “Multifunctional nanoplatforms for subcellular delivery of drugs in cancer therapy,” Progress in Materials Science, vol. 107, article 100599, 2020

135

Lin

, Bao

Y. W.

, and Wu

F. G.

, “Improving the phototherapeutic efficiencies of molecular and nanoscale materials by targeting mitochondria,” Molecules, vol. 23, no. 11, article 3016, 2018

136

Hua

X. W.

, Bao

Y. W.

, and Wu

F. G.

, “Fluorescent carbon quantum dots with intrinsic nucleolus-targeting capability for nucleolus imaging and enhanced cytosolic and nuclear drug delivery,” ACS Applied Materials & Interfaces, vol. 10, no. 13, pp. 10664–10677, 2018

137

Gao

, Jiang

Y. W.

, Yang

, and Wu

F. G.

, “Mitochondria-targetable carbon quantum dots for differentiating cancerous cells from normal cells,” Nanoscale, vol. 9, no. 46, pp. 18368–18378, 2017

138

Hua

X. W.

, Bao

Y. W.

, Chen

, and Wu

F. G.

, “Carbon quantum dots with intrinsic mitochondrial targeting ability for mitochondria-based theranostics,” Nanoscale, vol. 9, no. 30, pp. 10948–10960, 2017

139

Hua

X. W.

, Bao

Y. W.

, Zeng

, and Wu

F. G.

, “Nucleolus-targeted red emissive carbon dots with polarity-sensitive and excitation-independent fluorescence emission: high-resolution cell imaging and in vivo tracking,” ACS Applied Materials & Interfaces, vol. 11, no. 36, pp. 32647–32658, 2019

140

Cao

, Wu

, Zhang

, Meng

, Dai

, Wang

, Dong

, and Zhang

, “Engineered exosome-mediated near-infrared-II region V₂C quantum dot delivery for nucleus-target low-temperature photothermal therapy,” ACS Nano, vol. 13, no. 2, pp. 1499–1510, 2019

141

Liu

, Qiu

, Liao

, Rees

T. W.

, Chen

, Zhao

, Ji

, and Chao

, “Nucleus-targeting ultrasmall ruthenium(IV) oxide nanoparticles for photoacoustic imaging and low-temperature photothermal therapy in the NIR-II window,” Chemical Communications, vol. 56, no. 20, pp. 3019–3022, 2020

142

Jiang

, Yuan

, Wang

, Wei

, Sun

, Akakuru

O. U.

, Li

, and Wu

, “Near-infrared heptamethine cyanine dye-based nanoscale coordination polymers with intrinsic nucleus-targeting for low temperature photothermal therapy,” Nano Today, vol. 34, article 100910, 2020

143

Qiu

, Wang

, Rees

T. W.

, Ji

, Zhang

, and Chao

, “A mitochondria-targeting photothermogenic nanozyme for MRI-guided mild photothermal therapy,” Chemical Communications, vol. 54, no. 100, pp. 14108–14111, 2018

144

Ali

M. R. K.

, Wu

, Tang

, Xiao

, Chen

, Han

, Fang

, Wu

, and El-Sayed

M. A.

, “Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 28, pp. E5655–E5663, 2017

145

Bao

Y. W.

, Hua

X. W.

, Chen

, and Wu

F. G.

, “Platinum-doped carbon nanoparticles inhibit cancer cell migration under mild laser irradiation: multi-organelle-targeted photothermal therapy,” Biomaterials, vol. 183, pp. 30–42, 2018

146

Datta

N. R.

, Ordóñez

S. G.

, Gaipl

U. S.

, Paulides

M. M.

, Crezee

, Gellermann

, Marder

, Puric

, and Bodis

, “Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future,” Cancer Treatment Reviews, vol. 41, no. 9, pp. 742–753, 2015

147

Song

C. W.

, Shakil

, Osborn

J. L.

, and Iwata

, “Tumour oxygenation is increased by hyperthermia at mild temperatures,” International Journal of Hyperthermia, vol. 25, no. 2, pp. 91–95, 2009

148

Song

C. W.

, Park

H. J.

, Lee

C. K.

, and Griffin

, “Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment,” International Journal of Hyperthermia, vol. 21, no. 8, pp. 761–767, 2005

149

Sun

, Li

X. F.

, Russell

, Xing

, Urano

, Li

G. C.

, Humm

J. L.

, and Ling

C. C.

, “Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual-tracer immunohistochemistry,” Radiotherapy and Oncology, vol. 88, no. 2, pp. 269–276, 2008

150

Ding

, Chen

, Gao

, Jiang

, Zhang

, Li

, Xiao

, Lee

S. S.

, and Chen

, “Engineered nanomedicines with enhanced tumor penetration,” Nano Today, vol. 29, article 100800, 2019

151

Pérez-Herrero

, and Fernández-Medarde

, “Advanced targeted therapies in cancer: drug nanocarriers, the future of chemotherapy,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 93, pp. 52–79, 2015

152

Zhu

Y. X.

, Jia

H. R.

, Duan

Q. Y.

, Liu

, Yang

, Liu

, and Wu

F.-G.

, “Photosensitizer-doped and plasma membrane-responsive liposomes for nuclear drug delivery and multidrug resistance reversal,” ACS Applied Materials & Interfaces, vol. 12, no. 33, pp. 36882–36894, 2020

153

Bao

Y. W.

, Hua

X. W.

, Zeng

, and Wu

F. G.

, “Bacterial template synthesis of multifunctional nanospindles for glutathione detection and enhanced cancer-specific chemo-chemodynamic therapy,” Research, vol. 2020, article 9301215, –15, 2020

154

Zhang

, Chen

, Wang

H. Y.

, Jia

H. R.

, and Wu

F. G.

, “Supramolecular nanogel-based universal drug carriers formed by “soft−hard” co-assembly: accurate cancer diagnosis and hypoxia-activated cancer therapy,” Advanced Therapeutics, vol. 2, no. 5, article 1800140, 2019

155

Patel

N. R.

, Pattni

B. S.

, Abouzeid

A. H.

, and Torchilin

V. P.

, “Nanopreparations to overcome multidrug resistance in cancer,” Advanced Drug Delivery Reviews, vol. 65, no. 13−14, pp. 1748–1762, 2013

156

Yang

, Chen

, and Shi

, “Tumor-specific chemotherapy by nanomedicine-enabled differential stress sensitization,” Angewandte Chemie International Edition, vol. 59, no. 24, pp. 9693–9701, 2020

157

, Zhang

, Assaraf

Y. G.

, Zhao

, Xu

, Xie

, Yang

D.-H.

, and Chen

Z.-S.

, “Overcoming ABC transporter-mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies,” Drug Resistance Updates, vol. 27, pp. 14–29, 2016

158

Zhang

, Wang

, and Chen

, “Near-infrared light-mediated nanoplatforms for cancer thermo-chemotherapy and optical imaging,” Advanced Materials, vol. 25, no. 28, pp. 3869–3880, 2013

159

Sherlock

S. P.

, Tabakman

S. M.

, Xie

, and Dai

, “Photothermally enhanced drug delivery by ultrasmall multifunctional FeCo/graphitic shell nanocrystals,” ACS Nano, vol. 5, no. 2, pp. 1505–1512, 2011

160

Wang

, Liu

, Wang

, Cao

, Ji

, Wu

, Xu

, Bai

, Miao

, Chen

, and Zhao

, “Gd-hybridized plasmonic Au-nanocomposites enhanced tumor-interior drug permeability in multimodal imaging-guided therapy,” Advanced Materials, vol. 28, no. 40, pp. 8950–8958, 2016

161

Dong

, Liu

, Li

, Ren

, and Qu

, “Hydrophobic anticancer drug delivery by a 980 nm laser-driven photothermal vehicle for efficient synergistic therapy of cancer cells in vivo,” Advanced Materials, vol. 25, no. 32, pp. 4452–4458, 2013

162

Tian

, Zhang

, Zheng

, Yin

, Ruan

, Liu

, Zhou

, Yan

, Li

, Gu

, and Zhao

, “Multifunctional Rb_xWO₃ nanorods for simultaneous combined chemo-photothermal therapy and photoacoustic/CT imaging,” Small, vol. 10, no. 20, pp. 4160–4170, 2014

163

Y. C.

, Webb

J. A.

, Faley

, Shae

, Talbert

E. M.

, Lin

, Cutright

C. C.

, Wilson

J. T.

, Bellan

L. M.

, and Bardhan

, “Gold nanoantenna-mediated photothermal drug delivery from thermosensitive liposomes in breast cancer,” ACS Omega, vol. 1, no. 2, pp. 234–243, 2016

164

Wang

, Weng

, Fu

, Lin

, Fan

, Lu

, Qu

J. L.

, Chen

, Wang

, and Huang

, “Black phosphorus nanosheets for mild hyperthermia-enhanced chemotherapy and chemo-photothermal combination therapy,” Nanotheranostics, vol. 1, no. 2, pp. 208–216, 2017

165

Wang

, Huang

, He

, Chen

, Zou

, Li

, Lin

, Cai

, Xiao

, Zhang

, and Cheng

, “Multifunctional melanin-like nanoparticles for bone-targeted chemo-photothermal therapy of malignant bone tumors and osteolysis,” Biomaterials, vol. 183, pp. 10–19, 2018

166

Dong

, Gong

, Gao

, Zhu

, Sun

, Feng

, Fu

, Li

, and Liu

, “Polydopamine nanoparticles as a versatile molecular loading platform to enable imaging-guided cancer combination therapy,” Theranostics, vol. 6, no. 7, pp. 1031–1042, 2016

167

, Yang

, Ke

, Wang

, Peng

, Hu

, and Yuan

, “Smart assembled human serum albumin nanocarrier enhanced breast cancer treatment and antitumor immunity by chemo-photothermal therapy,” ACS Biomaterials Science & Engineering, vol. 6, no. 5, pp. 3217–3229, 2020

168

Yuan

, Liu

, Song

, Wang

, Xie

, Yan

, Zhou

, Wei

, Sun

, and Zhao

, “Photoinduced mild hyperthermia and synergistic chemotherapy by one-pot-synthesized docetaxel-loaded poly(lactic-co-glycolic acid)/polypyrrole nanocomposites,” ACS Applied Materials & Interfaces, vol. 8, no. 37, pp. 24445–24454, 2016

169

Geng

, Zhao

, Zhan

, Zhao

, and Yang

, “Injectable in situ forming hydrogels of thermosensitive polypyrrole nanoplatforms for precisely synergistic photothermo-chemotherapy,” ACS Applied Materials & Interfaces, vol. 12, no. 7, pp. 7995–8005, 2020

170

, Bremner

D. H.

, Niu

, Shi

, Wang

, Tang

, and Zhu

L.-M.

, “Chemodrug-gated biodegradable hollow mesoporous organosilica nanotheranostics for multimodal imaging-guided low-temperature photothermal therapy/chemotherapy of cancer,” ACS Applied Materials & Interfaces, vol. 10, no. 49, pp. 42115–42126, 2018

171

Wang

, Lin

, Wang

, Hu

, Ji

, Hou

, Zhao

, Wu

, and Chen

, “Novel insights into combating cancer chemotherapy resistance using a plasmonic nanocarrier: enhancing drug sensitiveness and accumulation simultaneously with localized mild photothermal stimulus of femtosecond pulsed laser,” Advanced Functional Materials, vol. 24, no. 27, pp. 4229–4239, 2014

172

, Ding

, Qian

, Zhang

, and Dong

C. M.

, “Dual drug-paired polyprodrug nanotheranostics reverse multidrug resistant cancers via mild photothermal-cocktail chemotherapy,” Journal of Materials Chemistry B, vol. 7, no. 35, pp. 5306–5319, 2019

173

Zhu

Y. D.

, Chen

S. P.

, Zhao

, Yang

, Chen

X.-Q.

, Sun

, Fan

H.-S.

, and Zhang

X.-D.

, “PPy@MIL-100 nanoparticles as a pH- and near-IR-irradiation-responsive drug carrier for simultaneous photothermal therapy and chemotherapy of cancer cells,” ACS Applied Materials & Interfaces, vol. 8, no. 50, pp. 34209–34217, 2016

174

, Je

J. Y.

, Moorthy

M. S.

, Seo

, and Cho

W. H.

, “pH and NIR-light-responsive magnetic iron oxide nanoparticles for mitochondria-mediated apoptotic cell death induced by chemo-photothermal therapy,” International Journal of Pharmaceutics, vol. 531, no. 1, pp. 1–13, 2017

175

Song

, Chong

, Fu

, Ning

, Shen

, and Zhang

, “HP-β-CD functionalized Fe₃O₄/CNPs-based theranostic nanoplatform for pH/NIR responsive drug release and MR/NIRFL imaging-guided synergetic chemo/photothermal therapy of tumor,” ACS Applied Materials & Interfaces, vol. 10, no. 40, pp. 33867–33878, 2018

176

, Huang

, Fan

, Wang

, Liu

, Wang

, Zhang

, Hu

, Liu

, Niu

, Leapman

R. D.

, Lu

, and Chen

, “Tri-stimuli-responsive biodegradable theranostics for mild hyperthermia enhanced chemotherapy,” Biomaterials, vol. 126, pp. 39–48, 2017

177

Zhang

, Zhao

, Chen

, Wang

, Zhang

, Wang

, Wei

, Zhang

, Rong

, Weng

, Hao

, Li

, Hou

X.-Q.

, Kang

, Zhao

, Wang

, Zhao

, Yu

, Wu

Q.-P.

, Liang

X.-J.

, and Xiao

, “Near-infrared light irradiation induced mild hyperthermia enhances glutathione depletion and DNA interstrand cross-link formation for efficient chemotherapy,” ACS Nano, vol. 14, no. 11, pp. 14831–14845, 2020

178

Chakraborty

, and Jana

N. R.

, “Clathrin to lipid raft-endocytosis via controlled surface chemistry and efficient perinuclear targeting of nanoparticle,” The Journal of Physical Chemistry Letters, vol. 6, no. 18, pp. 3688–3697, 2015

179

Shen

, Zhu

, Huo

, Yang

, Xue

, and Xia

, “A hybrid nanomaterial for the controlled generation of free radicals and oxidative destruction of hypoxic cancer cells,” Angewandte Chemie International Edition, vol. 56, no. 30, pp. 8801–8804, 2017

180

Ouyang

, Liu

, Ruan

, Liu

, Guo

, Cai

, Yu

, Pang

, and Shen

, “Localized free radicals burst triggered by NIR-II light for augmented low-temperature photothermal therapy,” ACS Applied Materials & Interfaces, vol. 11, no. 42, pp. 38555–38567, 2019

181

Cheng

, Zhang

, Liu

, Xia

L.-Y.

, Jiang

Y.-W.

, Gao

, Wang

H.-Y.

, Li

Y.-H.

, Ma

, Ran

H.-H.

, and Wu

F.-G.

, “Sequential treatment of cell cycle regulator and nanoradiosensitizer achieves enhanced radiotherapeutic outcome,” ACS Applied Bio Materials, vol. 2, no. 5, pp. 2050–2059, 2019

182

Begg

A. C.

, Stewart

F. A.

, and Vens

, “Strategies to improve radiotherapy with targeted drugs,” Nature Reviews Cancer, vol. 11, no. 4, pp. 239–253, 2011

183

Xiao

, Zheng

, Bu

, Ge

, Zhang

, Chen

, Xing

, Ren

, Fan

, Zhao

, Hua

, and Shi

, “A core/satellite multifunctional nanotheranostic for in vivo imaging and tumor eradication by radiation/photothermal synergistic therapy,” Journal of the American Chemical Society, vol. 135, no. 35, pp. 13041–13048, 2013

184

, Jiang

Y. W.

, Zhang

, Wu

, Myers

J. N.

, Liu

, Jin

, Gu

, He

, Wu

F. G.

, and Chen

, “Enhanced radiosensitization of gold nanospikes via hyperthermia in combined cancer radiation and photothermal therapy,” ACS Applied Materials & Interfaces, vol. 8, no. 42, pp. 28480–28494, 2016

185

Buckway

, Frazier

, Gormley

A. J.

, Ray

, and Ghandehari

, “Gold nanorod-mediated hyperthermia enhances the efficacy of HPMA copolymer-⁹⁰Y conjugates in treatment of prostate tumors,” Nuclear Medicine and Biology, vol. 41, no. 3, pp. 282–289, 2014

186

Chen

, Zhong

, Yi

, Huang

, Ning

, Liu

, Ge

, Chai

, Liu

, and Yang

, “Radionuclide ¹³¹I labeled reduced graphene oxide for nuclear imaging guided combined radio- and photothermal therapy of cancer,” Biomaterials, vol. 66, pp. 21–28, 2015

187

Cheng

, Yuan

, Shen

, Yi

, Gong

, Yang

, and Liu

, “Bottom-up synthesis of metal-ion-doped WS₂ nanoflakes for cancer theranostics,” ACS Nano, vol. 9, no. 11, pp. 11090–11101, 2015

188

, Wang

, Zhang

, Liu

, Zhu

, Yu

, Zhu

, Peng

, and Chen

, “Thiol-capped Bi nanoparticles as stable and all-in-one type theranostic nanoagents for tumor imaging and thermoradiotherapy,” Biomaterials, vol. 161, pp. 279–291, 2018

189

Song

, Wang

, Zhu

, Cheng

, Wang

, Tan

, Lian

, and Li

, “Biomodal tumor-targeted and redox-responsive Bi₂Se₃ hollow nanocubes for MSOT/CT imaging guided synergistic low-temperature photothermal radiotherapy,” Advanced Healthcare Materials, vol. 8, no. 16, article 1900250, 2019

190

Wang

, Riedinger

, Li

, Fu

, Liu

, Li

, Liu

, Tan

, Barthel

M. J.

, Pugliese

, De Donato

, D’Abbusco

M. S.

, Meng

, Manna

, Meng

, and Pellegrino

, “Plasmonic copper sulfide nanocrystals exhibiting near-infrared photothermal and photodynamic therapeutic effects,” ACS Nano, vol. 9, no. 2, pp. 1788–1800, 2015

191

Chen

, Ouyang

, Liu

, Chen

, Zeng

, Sheng

, Liu

, Han

, Wang

, Li

, Deng

, Liu

Y.-N.

, and Guo

, “Black phosphorus nanosheet-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer,” Advanced Materials, vol. 29, no. 5, article 1603864, 2017

192

, Zhou

, Zhao

, Yu

, Zhou

, Liu

, Huang

, and Zhao

, “Photothermally responsive conjugated polymeric singlet oxygen carrier for phase change-controlled and sustainable phototherapy for hypoxic tumor,” Research, vol. 2020, article 5351848, –14, 2020

193

Zeng

, Pan

, Zou

, Zhang

, Tian

, Teng

, Wang

, Ren

, Xiao

, Zhang

, Li

, Lu

, and Wu

, “808 nm-excited upconversion nanoprobes with low heating effect for targeted magnetic resonance imaging and high-efficacy photodynamic therapy in HER2-overexpressed breast cancer,” Biomaterials, vol. 103, pp. 116–127, 2016

194

Zhang

, Meng

, Cao

, Yang

, Dong

, Zhang

, Lu

, Shi

, and Zhang

, “Metal–organic framework nanoshuttle for synergistic photodynamic and low-temperature photothermal therapy,” Advanced Functional Materials, vol. 28, no. 42, article 1804634, 2018

195

Gai

, Yang

, He

, Lin

, Jin

, and Xing

, “Recent advances in functional nanomaterials for light-triggered cancer therapy,” Nano Today, vol. 19, pp. 146–187, 2018

196

Liu

, Wang

, Cui

, Gong

, Liang

, Shi

, Li

, Sun

, and Liu

, “Combined photothermal and photodynamic therapy delivered by PEGylated MoS₂ nanosheets,” Nanoscale, vol. 6, no. 19, pp. 11219–11225, 2014

197

Hua

X. W.

, Bao

Y. W.

, Zeng

, and Wu

F. G.

, “Ultrasmall all-in-one nanodots formed via carbon dot-mediated and albumin-based synthesis: multimodal imaging-guided and mild laser-enhanced cancer therapy,” ACS Applied Materials & Interfaces, vol. 10, no. 49, pp. 42077–42087, 2018

198

Sun

, Chen

, Jiang

, Tang

, Wang

, Li

, Liu

, Wu

, and Lin

, “Ce6-modified carbon dots for multimodal-imaging-guided and single-NIR-laser-triggered photothermal/photodynamic synergistic cancer therapy by reduced irradiation power,” ACS Applied Materials & Interfaces, vol. 11, no. 6, pp. 5791–5803, 2019

199

, Niu

, Bremner

D. H.

, Nie

, Fu

, Li

, and Zhu

L.‐. M.

, “A tumor microenvironment-responsive biodegradable mesoporous nanosystem for anti-inflammation and cancer theranostics,” Advanced Healthcare Materials, vol. 9, no. 2, article 1901307, 2020

200

, Peng

, Tan

, Wu

, Shi

, Qu

, Wei

X. W.

, and Qian

Z. Y.

, “Mild photothermal therapy/photodynamic therapy/chemotherapy of breast cancer by Lyp-1 modified docetaxel/IR820 co-loaded micelles,” Biomaterials, vol. 106, pp. 119–133, 2016

201

Liang

, Deng

, Ma

, Cheng

, and Lin

, “Recent advances in nanomaterial-assisted combinational sonodynamic cancer therapy,” Advanced Materials, vol. 32, no. 47, article 2003214, 2020

202

Gong

, Cheng

, Yang

, Gong

, Ni

, Bai

, Wang

, Chen

, and Liu

, “Preparation of TiH_1.924 nanodots by liquid-phase exfoliation for enhanced sonodynamic cancer therapy,” Nature Communications, vol. 11, no. 1, article 3712, 2020

203

Tang

, Zhao

, Ni

, Liu

, Zhang

, Wang

, Zhang

, Gao

, Yao

, and Bu

, “Pyroelectric nanoplatform for NIR-II-triggered photothermal therapy with simultaneous pyroelectric dynamic therapy,” Materials Horizons, vol. 5, no. 5, pp. 946–952, 2018

204

Guo

, Zhang

, Sun

, Jia

H.-R.

, Zhu

Y.-X.

, Zhang

, Zhou

, and Wu

F.-G.

, “Metal–phenolic network-based nanocomplexes that evoke ferroptosis by apoptosis: promoted nuclear drug influx and reversed drug resistance of cancer,” Chemistry of Materials, vol. 31, no. 24, pp. 10071–10084, 2019

205

Tang

, Liu

, He

, and Bu

, “Chemodynamic therapy: tumour microenvironment-mediated Fenton and Fenton-like reactions,” Angewandte Chemie International Edition, vol. 58, no. 4, pp. 946–956, 2019

206

Deng

, and Englehardt

J. D.

, “Treatment of landfill leachate by the Fenton process,” Water Research, vol. 40, no. 20, pp. 3683–3694, 2006

207

Guan

, Wang

, Li

, Zhang

, Cui

, Lu

, Zou

, and Hu

, ““Transformed” Fe₃S₄ tetragonal nanosheets: a high-efficiency and body-clearable agent for magnetic resonance imaging guided photothermal and chemodynamic synergistic therapy,” Nanoscale, vol. 10, no. 37, pp. 17902–17911, 2018

208

She

, Peng

, Liu

, Huang

, Zheng

, Lu

, Geng

, and Yin

, “Biomimic FeS₂ nanodrug with hypothermal photothermal effect by clinical approved NIR-II light for augmented chemodynamic therapy,” Chemical Engineering Journal, vol. 400, article 125933, 2020

209

Guo

, Wang

, and Yang

, “Photoacoustic imaging guided photothermal and chemodynamic combined therapy for cancer using “all in one” W₁₈O₄₉ nanorod agent,” Journal of Biomedical Nanotechnology, vol. 15, no. 10, pp. 2090–2099, 2019

210

Qian

, and Matson

J. B.

, “Gasotransmitter delivery via self-assembling peptides: treating diseases with natural signaling gases,” Advanced Drug Delivery Reviews, vol. 110–111, pp. 137–156, 2017

211

Carpenter

A. W.

, and Schoenfisch

M. H.

, “Nitric oxide release: part II. Therapeutic applications,” Chemical Society Reviews, vol. 41, no. 10, pp. 3742–3752, 2012

212

, Liu

L. Z.

, Loizidou

, Ahmed

, and Charles

I. G.

, “The role of nitric oxide in cancer,” Cell Research, vol. 12, no. 5–6, pp. 311–320, 2002

213

Fan

, Yung

B. C.

, and Chen

, “Stimuli-responsive NO release for on-demand gas-sensitized synergistic cancer therapy,” Angewandte Chemie International Edition, vol. 57, no. 28, pp. 8383–8394, 2018

214

Zhang

, Du

, Guo

, Yu

, Gao

, Yin

, Zhu

, Gu

, and Zhao

, “Efficient near infrared light triggered nitric oxide release nanocomposites for sensitizing mild photothermal therapy,” Advanced Science, vol. 6, no. 3, article 1801122, 2019

215

You

, Li

, Dong

, Ning

, Zhang

, Yao

, and Wang

, “Low-temperature trigger nitric oxide nanogenerators for enhanced mild photothermal therapy,” ACS Biomaterials Science & Engineering, vol. 6, no. 3, pp. 1535–1542, 2020

216

Feng

, Yang

, Shi

, Tan

, Peng

, Wang

, and Liu

, “Polyethylene glycol and polyethylenimine dual-functionalized nano-graphene oxide for photothermally enhanced gene delivery,” Small, vol. 9, no. 11, pp. 1989–1997, 2013

217

Lyu

, Cui

, Sun

, Miao

, Duan

, and Pu

, “Dendronized semiconducting polymer as photothermal nanocarrier for remote activation of gene expression,” Angewandte Chemie International Edition, vol. 129, no. 31, pp. 9283–9287, 2017

218

Liu

, Shu

, Li

, Chen

, Zhang

, Pan

, Li

, Gong

, Wang

, Wu

, Dou

, and Chang

, “Human HSP70 promoter-based Prussian blue nanotheranostics for thermo-controlled gene therapy and synergistic photothermal ablation,” Advanced Functional Materials, vol. 28, no. 32, article 1802026, 2018

219

Chen

, Chen

, Xin

, Wan

, and Ping

, “Near-infrared optogenetic engineering of photothermal nanoCRISPR for programmable genome editing,” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 5, pp. 2395–2405, 2020

220

Haviv

Y. S.

, Blackwell

J. L.

, Li

, Wang

, Lei

, and Curiel

D. T.

, “Heat shock and heat shock protein 70i enhance the oncolytic effect of replicative adenovirus,” Cancer Research, vol. 61, no. 23, pp. 8361–8365, 2001

221

Insulated hsp70B

′

promoter: stringent heat-inducible activity in replication-deficient, but not replication-competent adenoviruses

Rohmer

, Mainka

, Knippertz

, Hesse

, and Nettelbeck

D. M.

, “Insulated hsp70B′ promoter: stringent heat-inducible activity in replication-deficient, but not replication-competent adenoviruses,” The Journal of Gene Medicine, vol. 10, no. 4, pp. 340–354, 2008

222

Thorne

S. H.

, Brooks

, Lee

Y. L.

, Au

, Eng

L. F.

, and Reid

, “Effects of febrile temperature on adenoviral infection and replication: implications for viral therapy of cancer,” Journal of Virology, vol. 79, no. 1, pp. 581–591, 2005

223

Jung

B. K.

, Lee

Y. K.

, Hong

, Ghandehari

, and Yun

C. O.

, “Mild hyperthermia induced by gold nanorod-mediated plasmonic photothermal therapy enhances transduction and replication of oncolytic adenoviral gene delivery,” ACS Nano, vol. 10, no. 11, pp. 10533–10543, 2016

224

Rosati

, Graziano

, De Laurenzi

, Pascale

, and Turco

M. C.

, “BAG3: a multifaceted protein that regulates major cell pathways,” Cell Death & Disease, vol. 2, no. 4, article e141, 2011

225

Wang

B. K.

, Yu

X. F.

, Wang

J. H.

, Li

Z.-B.

, Li

P.-H.

, Wang

, Song

, Chu

P. K.

, and Li

, “Gold-nanorods-siRNA nanoplex for improved photothermal therapy by gene silencing,” Biomaterials, vol. 78, pp. 27–39, 2016

226

Mellman

, Coukos

, and Dranoff

, “Cancer immunotherapy comes of age,” Nature, vol. 480, no. 7378, pp. 480–489, 2011

227

Pardoll

D. M.

, “The blockade of immune checkpoints in cancer immunotherapy,” Nature Reviews Cancer, vol. 12, no. 4, pp. 252–264, 2012

228

Ferrone

, and Dranoff

, “Dual roles for immunity in gastrointestinal cancers,” Journal of Clinical Oncology, vol. 28, no. 26, pp. 4045–4051, 2010

229

Gajewski

T. F.

, Schreiber

, and Fu

Y. X.

, “Innate and adaptive immune cells in the tumor microenvironment,” Nature Immunology, vol. 14, no. 10, pp. 1014–1022, 2013

230

Chen

D. S.

, and Mellman

, “Oncology meets immunology: the cancer-immunity cycle,” Immunity, vol. 39, no. 1, pp. 1–10, 2013

231

Beatty

G. L.

, and Gladney

W. L.

, “Immune escape mechanisms as a guide for cancer immunotherapy,” Clinical Cancer Research, vol. 21, no. 4, pp. 687–692, 2015

232

Hargadon

K. M.

, Johnson

C. E.

, and Williams

C. J.

, “Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors,” International Immunopharmacology, vol. 62, pp. 29–39, 2018

233

Patel

S. A.

, and Minn

A. J.

, “Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies,” Immunity, vol. 48, no. 3, pp. 417–433, 2018

234

O’Donnell

J. S.

, Teng

M. W. L.

, and Smyth

M. J.

, “Cancer immunoediting and resistance to T cell-based immunotherapy,” Nature Reviews Clinical Oncology, vol. 16, no. 3, pp. 151–167, 2019

235

Riley

R. S.

, June

C. H.

, Langer

, and Mitchell

M. J.

, “Delivery technologies for cancer immunotherapy,” Nature Reviews Drug Discovery, vol. 18, no. 3, pp. 175–196, 2019

236

Romero

, Banchereau

, Bhardwaj

, Cockett

, Disis

M. L.

, Dranoff

, Gilboa

, Hammond

S. A.

, Hershberg

, Korman

A. J.

, Kvistborg

, Melief

, Mellman

, Palucka

A. K.

, Redchenko

, Robins

, Sallusto

, Schenkelberg

, Schoenberger

, Sosman

, Türeci

Ö.

, Van den Eynde

, Koff

, and Coukos

, “The human vaccines project: a roadmap for cancer vaccine development,” Science Translational Medicine, vol. 8, no. 334, article 334ps9, 2016

237

Caruana

, Savoldo

, Hoyos

, Weber

, Liu

, Kim

E. S.

, Ittmann

M. M.

, Marchetti

, and Dotti

, “Heparanase promotes tumor infiltration and antitumor activity of CAR- redirected T lymphocytes,” Nature Medicine, vol. 21, no. 5, pp. 524–529, 2015

238

Wang

, Ye

, Hu

, Bellotti

, and Gu

, “Tailoring biomaterials for cancer immunotherapy: emerging trends and future outlook,” Advanced Materials, vol. 29, no. 29, article 1606036, 2017

239

, He

, Dong

, Liu

, Wang

, Li

, Ren

, Shi

, and Li

, “Fever-inspired immunotherapy based on photothermal CpG nanotherapeutics: the critical role of mild heat in regulating tumor microenvironment,” Advanced Science, vol. 5, no. 6, article 1700805, 2018

240

Vo-Dinh

, Inman

, Maccarini

, Palmer

, and Liu

, “Synergistic immuno photothermal nanotherapy (SYMPHONY) to treat metastatic cancers and induce anti-cancer vaccine effect,” Proceedings of SPIE, vol. 10484, article UNSP 1048408, 2018

241

Liu

, Crawford

B. M.

, and Vo-Dinh

, “Gold nanoparticles-mediated photothermal therapy and immunotherapy,” Immunotherapy, vol. 10, no. 13, pp. 1175–1188, 2018

242

Chen

, Hu

, Dukhovlinova

, Chen

, Ahn

, Wang

, Ogunnaike

E. A.

, Ligler

F. S.

, Dotti

, and Gu

, “Photothermal therapy promotes tumor infiltration and antitumor activity of CAR T cells,” Advanced Materials, vol. 31, no. 23, article 1900192, 2019

243

Deng

, Liang

, Yang

, and Shao

, “Polarization and function of tumor-associated macrophages mediate graphene oxide-induced photothermal cancer therapy,” Journal of Photochemistry and Photobiology, B: Biology, vol. 208, article 111913, 2020

244

Chu

K. F.

, and Dupuy

D. E.

, “Thermal ablation of tumours: biological mechanisms and advances in therapy,” Nature Reviews Cancer, vol. 14, no. 3, pp. 199–208, 2014

245

Lin

, Wei

, Hurt

E. M.

, Green

M. D.

, Zhao

, Vatan

, Szeliga

, Herbst

, Harms

P. W.

, Fecher

L. A.

, Vats

, Chinnaiyan

A. M.

, Lao

C. D.

, Lawrence

T. S.

, Wicha

, Hamanishi

, Mandai

, Kryczek

, and Zou

, “Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression,” Journal of Clinical Investigation, vol. 128, no. 2, pp. 805–815, 2018

246

Anker

J. F.

, Naseem

A. F.

, Mok

, Schaeffer

A. J.

, Abdulkadir

S. A.

, and Thumbikat

, “Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy,” Nature Communications, vol. 9, no. 1, article 1591, 2018

247

Lau

, Cheung

, Navarro

, Lianoglou

, Haley

, Totpal

, Sanders

, Koeppen

, Caplazi

, McBride

, Chiu

, Hong

, Grogan

, Javinal

, Yauch

, Irving

, Belvin

, Mellman

, Kim

J. M.

, and Schmidt

, “Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice,” Nature Communications, vol. 8, no. 1, article 14572, 2017

248

Sanmamed

M. F.

, and Chen

, “A paradigm shift in cancer immunotherapy: from enhancement to normalization,” Cell, vol. 175, no. 2, pp. 313–326, 2018

249

Wang

, Sun

, Ye

, Hu

, Bomba

H. N.

, and Gu

, “In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy,” Nature Biomedical Engineering, vol. 1, no. 2, article 0011, 2017

250

Wang

, Wang

, Liu

, Yu

, Jiao

, Feng

, Zhou

, Fu

, Yin

, Zhang

, Zhou

, and Li

, “Acid-activatable versatile micelleplexes for PD-L1 blockade-enhanced cancer photodynamic immunotherapy,” Nano Letters, vol. 16, no. 9, pp. 5503–5513, 2016

251

Peng

, Xiao

, Li

, Yang

, Tan

, Jia

, Qu

, and Qian

, “Photosensitizer micelles together with IDO inhibitor enhance cancer photothermal therapy and immunotherapy,” Advanced Science, vol. 5, no. 5, article 1700891, 2018

252

Chen

, Cen

, Ren

, Wang

, Cai

, Huang

, Di Silvio

, Li

, and Han

, “Bismuth embedded silica nanoparticles loaded with autophagy suppressant to promote photothermal therapy,” Biomaterials, vol. 221, article 119419, 2019

253

, Liu

, and Chen

, “Remote control and modulation of cellular events by plasmonic gold nanoparticles: implications and opportunities for biomedical applications,” ACS Nano, vol. 11, no. 3, pp. 2403–2409, 2017

254

Jiang

, von Roemeling

C. A.

, Chen

, Qie

, Liu

, Chen

, and Kim

B. Y. S.

, “Designing nanomedicine for immuno-oncology,” Nature Biomedical Engineering, vol. 1, no. 2, article 0029, 2017

255

Deng

, Guan

, Qing

, Yang

, Que

, Tan

, Liang

, Zhang

, Wang

, Liu

, Zhao

, and Shao

, “Ultrafast low-temperature photothermal therapy activates autophagy and recovers immunity for efficient antitumor treatment,” ACS Applied Materials & Interfaces, vol. 12, no. 4, pp. 4265–4275, 2020

256

Huang

, Li

, Du

, Zhang

, Wang

, Ding

, Yang

, Meng

, Tu

, Luo

, and Sun

, “Mild photothermal therapy potentiates anti-PD-L1 treatment for immunologically cold tumors via an all-in-one and all-in-control strategy,” Nature Communications, vol. 10, no. 1, article 4871, 2019

257

Guo

, Zhang

, Liu

, Gao

, Zhang

, Hu

, Li

, Zhang

, Zhou

, Bai

, Wang

, Li

, Liu

, Gu

, and Chen

, “Few-layer bismuthene for checkpoint knockdown enhanced cancer immunotherapy with rapid clearance and sequentially triggered one-for-all strategy,” ACS Nano, vol. 14, no. 11, pp. 15700–15713, 2020

258

Melief

C. J. M.

, van Hall

, Arens

, Ossendorp

, and van der Burg

S. H.

, “Therapeutic cancer vaccines,” Journal of Clinical Investigation, vol. 125, no. 9, pp. 3401–3412, 2015

259

Melero

, Gaudernack

, Gerritsen

, Huber

, Parmiani

, Scholl

, Thatcher

, Wagstaff

, Zielinski

, Faulkner

, and Mellstedt

, “Therapeutic vaccines for cancer: an overview of clinical trials,” Nature Reviews Clinical Oncology, vol. 11, no. 9, pp. 509–524, 2014

260

Keenan

B. P.

, and Jaffee

E. M.

, “Whole cell vaccines–past progress and future strategies,” Seminars in Oncology, vol. 39, no. 3, pp. 276–286, 2012

261

Gubin

M. M.

, Artyomov

M. N.

, Mardis

E. R.

, and Schreiber

R. D.

, “Tumor neoantigens: building a framework for personalized cancer immunotherapy,” Journal of Clinical Investigation, vol. 125, no. 9, pp. 3413–3421, 2015

262

Chen

P. M.

, Pan

W. Y.

, Wu

C. Y.

, Yeh

C.-Y.

, Korupalli

, Luo

P.-K.

, Chou

C.-J.

, Chia

W.-T.

, and Sung

H.-W.

, “Modulation of tumor microenvironment using a TLR-7/8 agonist-loaded nanoparticle system that exerts low-temperature hyperthermia and immunotherapy for in situ cancer vaccination,” Biomaterials, vol. 230, article 119629, 2020

263

, Hagan C. T. IV, Vincent

B. G.

, and Wang

A. Z.

, “Emerging nano-/microapproaches for cancer immunotherapy,” Advanced Science, vol. 6, no. 6, article 1801847, 2019

264

Kawasaki

, and Kawai

, “Toll-like receptor signaling pathways,” Frontiers in Immunology, vol. 5, p. 461, 2014

265

Marabelle

, Kohrt

, Caux

, and Levy

, “Intratumoral immunization: a new paradigm for cancer therapy,” Clinical Cancer Research, vol. 20, no. 7, pp. 1747–1756, 2014

266

Galluzzi

, Buqué

, Kepp

, Zitvogel

, and Kroemer

, “Immunogenic cell death in cancer and infectious disease,” Nature Reviews Immunology, vol. 17, no. 2, pp. 97–111, 2017

267

, Nie

, Xia

, Liu

, Huang

, Wang

, and Chen

, “Designing bioinspired 2D MoSe₂ nanosheet for efficient photothermal-triggered cancer immunotherapy with reprogramming tumor-associated macrophages,” Advanced Functional Materials, vol. 29, no. 30, article 1901240, 2019

268

Chen

H. Y.

, Xu

, Li

L. F.

, Liu

X. X.

, Gao

J. X.

, and Bai

Y. R.

, “Inhibiting the CD8⁺ T cell infiltration in the tumor microenvironment after radiotherapy is an important mechanism of radioresistance,” Scientific Reports, vol. 8, no. 1, article 11934, 2018

269

Lan

, Ni

, Xu

, Veroneau

S. S.

, Song

, and Lin

, “Nanoscale metal−organic framework overcomes hypoxia for photodynamic therapy primed cancer immunotherapy,” Journal of the American Chemical Society, vol. 140, no. 17, pp. 5670–5673, 2018

270

Chang

M. C.

, Cheng

J. C. H.

, and Chiang

Y. C.

, “Local irradiation promotes antitumor immunity and abscopal effect of antigen-specific immunotherapy by enhancing dendritic cell maturation,” Cancer Research, vol. 77, no. 13, article 3674, 2017

271

Teng

, Kong

, Meng

, Yang

, and Yu

, “Radiotherapy combined with immune checkpoint blockade immunotherapy: achievements and challenges,” Cancer Letters, vol. 365, no. 1, pp. 23–29, 2015

272

Dong

, Cheng

, Zhu

, Liu

, Zhou

, Zhang

, Chen

, Mei

, Wang

, Su

, Liu

, Gu

, and Zhao

, “A heterojunction structured WO_2.9-WSe₂ nanoradiosensitizer increases local tumor ablation and checkpoint blockade immunotherapy upon low radiation dose,” ACS Nano, vol. 14, no. 5, pp. 5400–5416, 2020

273

Zhou

, Liu

, Zhang

, Jia

, and Li

, “DNA-templated porous nanoplatform towards programmed "double-hit" cancer therapy via hyperthermia and immunogenicity activation,” Biomaterials, vol. 219, article 119395, 2019

Appendix

Less

Year 2021 volume 2021 Issue 5

PDF

Cite this Article

BibTeX

Article Info

doi: 10.34133/2021/9816594

Receive Date：2021-01-03
Online Date：2026-10-27
Published：2021-05-20

Article Data

Affiliations

History

Received：2021-01-03
Accepted：2021-03-01

Funding

Ministry of Education of the People's Republic of China(GKE-KF202001)

National Natural Science Foundation of China(21673037)

Affiliations

State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, 2 Sipailou Road, Nanjing 210096, China

References

Share

https://castjournals.cast.org.cn/joweb/research/EN/10.34133/2021/9816594

Share to

Scan QR to access full text

Cite this article

BibTeX

Citations

表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Table 1 Strategies for low-temperature PTT for treating bacterial infections and promoting wound healing.

Applications	Strategies	Agents for strategies	PTAs	Reference
Antibiosis	Antimicrobial peptides	MagI	PDA	[58]
	NO-enhanced PDT	L-Arg and ICG	PDA	[59]
	Antibiotic therapy	Ofloxacin	QCS-MoS₂ nanoflakes	[60]
	Antibiotic therapy	Aminoglycoside antibiotics	Red phosphorus NPs	[61]

Wound healing	Bioactive ion-mediated treatment	Hap nanorods	PDA	[65]
		Hap	GO/NCD/Hap films	[66]
		FA	FA	[67]
	MSC-based therapy	MSCs	CuS@BSA NPs	[68]

Table 2 Strategies for low-temperature PTT for cancer treatments.

Strategies	Agents for strategies			PTAs	Reference
HSP downregulation	HSP inhibition	Small-molecule HSP inhibitors	GA	dc-IR825	[27]
				ICG	[93]
				Bi@ZIF-8 NPs	[94]
				HMCSs	[95]
				Semiconducting polymer	[96]
				BPQDs	[97]
				GO	[98]
			Qu	Qu-Fe^IIPs	[99]
			Qu	AuNRs	[100]
			17-AAG	Cypate	[101]
			VER-155008	AuNRs	[102]
			PES	PEDOT	[103]
			EGCG	Lu:Nd@NiS₂ NPs	[104]
			BIIB021	IR780	[105]
		siRNA HSP70 inhibitors		Cypate	[106]
				Gold nanoshells	[107]
				PDA	[108]
	Cancer starvation therapy	DC		GNRs	[113]
		GOx		ICG	[32]
				ICG	[117]
				PB NPs	[118]
		M-NS		M-NS	[119]
		siPKM2		ICG	[120]

Autophagy-mediated cancer therapy	Autophagy inhibition	CQ or chloroquine diphosphate		PDA	[129]
				PDA	[130]
				PDA	[131]
				PDA	[132]
	Autophagy augment	Beclin 1-derived peptide		PDA	[133]

Organelle-targeting strategies	Nucleus	TAT peptides		Pd nanosheets	[14]
		TAT peptides		Vanadium carbide QDs	[140]
		Chitosan-coated ruthenium(IV) oxide NPs		Chitosan-coated ruthenium(IV) oxide NPs	[141]
		Hf-HI-4COOH-based NCPs		Hf-HI-4COOH	[142]
	Mitochondrion	Lipophilic iridium(III)		Fe₃O₄ NPs	[143]
	Integrin and cytoskeleton	RGD peptides		AuNRs	[144]
	Multiple organelles	PEG-PtCNPs		PtCNPs	[145]

Table 3 Low-temperature PTT-involving synergistic therapies.

Therapeutic modality in combination with PTT	Agents (except PTAs)		PTAs	Reference
Chemotherapy	DOX	PEG	GC shell	[159]
		HA	Gd-hybridized plasmonic Au-nanocomposites	[160]
		PVP	Rb_xWO₃ nanorods	[162]
		Low-temperature-sensitive liposomes	Gold nanoantennas	[163]
		PEG	PDA and ICG	[166]
		HSA	ICG	[167]
		Poly(acrylic acid-b-N-isopropylamide-b-acrylic acid)	PPy	[169]
		Fe³⁺ carboxylate MOFs	PPy	[173]
		—	Au@SiO₂	[171]
		Meso-2,3-dimercaptosuccinic acid	Fe₃O₄	[174]
		Hydroxypropyl-β-cyclodextrin (HP-β-CD)	Fe₃O₄/carbon NPs	[175]
		Periodic mesoporous organosilica NPs	CuS	[176]
	Camptothecin		Hollow CuS NPs	[161]
	Paclitaxel and HSA		Black phosphorus nanosheets	[164]
	SN38 and alendronate		PDA	[165]
	DTX, PLGA, and PEG		PPy	[168]
	Gemcitabine, 17-AAG, hollow mesoporous organosilica nanocapsule, and PEG		ICG	[170]
	DOX and cisplatin		PDA	[172]
	Cisplatin and amphiphilic polymer containing Pt(IV) prodrugs and pendant iodides		IR780	[177]

RT	¹³¹I and PEG		RGO	[186]
	PEG		Gd³⁺-doped WS₂ nanoflakes	[187]
	PEG		Bi NPs	[188]
	HA and GA		Bi₂Se₃ HNCs	[189]

PDT	PEG and HSP70 siRNA		Zr-FeP MOF nanoshuttles	[194]
	Ce6 and PEG		MoS₂ nanosheets	[196]
	HPPH		BCCG nanodots	[197]
	Ce6		Amino-rich red emissive CDs	[198]
	HMONs, BSA, PEG, and 17-AAG		IrO₂	[199]
	DTX, mPEG-PCL, PCL-g-PEI, and Lyp-1		IR820	[200]

SDT	PVP		TiH_1.924 nanodots	[202]
PEDT	PVP		SnSe	[203]

CDT	PEG		FeS₂@RBCs	[208]
CDT	—		W₁₈O₄₉ nanorods	[209]

Gas therapy	BNN and Tween-20		Bi₂S₃ NPs	[214]
Gas therapy	S-nitrosothiol, PES, and PEG		Au@SiO₂	[215]

Gene therapy	HSP-regulated gene plasmids		Semiconducting backbones	[217]
	Therapeutic plasmid DNA and PEI		PB	[218]
	HSP-nuclease protein 9 (Cas9) plasmids		Cationic polymer-coated Au nanorods	[219]
	Oncolytic Ads		AuNRs	[223]
	BAG3-targeting siRNA oligomers		AuNRs	[225]

Immunotherapy	CSPG4-specific CAR T cells		ICG	[242]
	aPD-L1, folic acid, and SNX-2112		GO	[255]
	aPD-L1 and LG depot		IR820	[256]
	siRNA against PD-L1, mPEG, and PEI		Bismuthene	[257]
	R848 and GCS		PANI	[262]
	aPD-L1		WO_2.9-WSe₂-PEG NPs	[272]
	FeOOH nanodots and STA-9090		Cu-LDH	[43]
	Oxaliplatin and EGCG		PCS nanomaterials	[273]

Figure 1 Scheme illustrating the use of low-temperature PTT for antibiosis, wound healing, and cancer treatment via various strategies.

Figure 2 (a) Schematic illustration of NO-enhanced PDT and low-temperature PTT for biofilm eradication based on AI-MPDA NPs under NIR light irradiation. Reprinted with permission from Reference [59]. Copyright 2020, American Chemical Society. (b) Scheme of the synthesis of QCS-MoS₂-OFLX and the synergistic low-temperature photothermal/antibiotic therapy against MRSA bacteria. Reprinted with permission from Reference [60]. Copyright 2020, Springer. (c) Design of hot spring-mimetic hydrogel. (d) Application of the FA-NOCS hydrogel with “hot spring effect” for wound healing. (c, d) Reprinted with permission from Reference [67]. Copyright 2021, Elsevier Ltd. (e) Scheme illustrating the differentiation of MSCs that were treated with CuS@BSA (in the presence or absence of NIR light irradiation) or mild heating into fibroblasts, and the skin wound closure function of these MSC-containing systems. Reprinted with permission from Reference [68]. Copyright 2020, Ivyspring.

Figure 3 (a) Scheme illustrating the one-step synthesis of one-dimensional coordination polymer nanofibers. Reprinted with permission from Reference [93]. Copyright 2017, Wiley-VCH. (b) Fabrication and working mechanism of HSA/dc-IR825/GA NPs for synergistic molecular targeting-mediated mild-temperature PTT and chemotherapy. Reprinted with permission from Reference [27]. Copyright 2019, Wiley-VCH. (c) Mechanism of the ROS-mediated disassembly of Qu-Fe^IIPs. Reprinted with permission from Reference [99]. Copyright 2019, Elsevier Ltd. (d) Scheme showing the structure and components of the CA-micelles and their use for mutually synergistic MTT/PTT. Reprinted with permission from Reference [101]. Copyright 2017, Wiley-VCH. (e) Schematic illustration of the synthesis of PP-NGs. (f) Scheme showing the mechanism of low-temperature PTT realized by PP-NGs. (e, f) Reprinted with permission from Reference [108]. Copyright 2020, Elsevier Ltd.

Figure 4 (a) Scheme showing the use of GNR/HA-DC to sensitize cancer cells to mild PTT by interfering with the anaerobic glycolysis metabolism. Reprinted with permission from Reference [113]. Copyright 2017, American Chemical Society. (b) Scheme illustrating the transformation of GOIGLs upon NIR light irradiation. (c) Scheme depicting the mechanism of EEPT and low-temperature PTT. (b, c) Reprinted with permission from Reference [32]. Copyright 2020, Wiley-VCH. (d) Scheme showing the utilization of M-NS for cancer starvation therapy and PTT. Reprinted with permission from Reference [119]. Copyright 2019, Wiley-VCH.

Figure 5 (a) Scheme of the enhanced cancer therapeutic efficiency of mild PTT resulting from photothermal sensitization through CQ-mediated autophagy inhibition. Reprinted with permission from Reference [129]. Copyright 2017, Elsevier Ltd. (b) Multistep preparation process of the rattle-structured PDA@hm@CQ@GOx NP. (c) Schematic illustration of the working mechanism of PDA@hm@CQ@GOx NPs that can achieve enhanced low-temperature PTT under NIR light irradiation. (b, c) Reprinted with permission from Reference [131]. Copyright 2020, Ivyspring. (d) Scheme depicting the beclin 1-induced autophagy rendering cancer cells vulnerable to photothermal elimination. Reprinted with permission from Reference [133]. Copyright 2019, Elsevier Ltd. (e) Scheme illustrating the Hf-HI-4COOH NCP structure and nucleus-targeted low-temperature PTT. Reprinted with permission from Reference [142]. Copyright 2020, Elsevier Ltd. (f) Scheme depicting the synthesis of PEG-PtCNPs and PEG-PtCNPs-RITC and their application for multimodal imaging-guided and multiorganelle-targeted PTT. Reprinted with permission from Reference [145]. Copyright 2018, Elsevier Ltd.

Figure 6 (a) Scheme illustrating the enhancement of tumor-interior permeability accomplished by Gd-hybridized plasmonic Au-nanocomposites in multimodal imaging-guided cancer therapy. Reprinted with permission from Reference [160]. Copyright 2016, Wiley-VCH. (b) Discipline of defeating cancer cell drug resistance under fs-pulse laser irradiation. Reprinted with permission from Reference [171]. Copyright 2014, Wiley-VCH. (c) Scheme showing the construction and NIR light- and GSH-mediated dissociation of Pt-I-IR780 NPs. (d) Scheme showing the significantly elevated cancer treatment efficiency of Pt-I-IR780 NPs (compared with cisplatin) achieved via low-temperature PTT-enhanced chemotherapy. (c, d) Reprinted with permission from Reference [177]. Copyright 2020, American Chemical Society.

Figure 7 (a) Schematic illustration of the PEG-modified Gd³⁺-doped WS₂ nanoflake-mediated enhancement of RT and PTT under X-ray and NIR light irradiation. Reprinted with permission from Reference [187]. Copyright 2015, American Chemical Society. (b) Synthesis of BCCGH and its application for multimodal imaging and combined PTT and PDT. (c) Confocal images showing the localization of free HPPH and BCCGH in the different organelles of A549 cells. Hoechst 33342 (Hoechst), ER-Tracker Green (ER-Tracker), rhodamine 123 (Rhod-123), LysoTracker Green (LysoTracker), Golgi-Tracker Green (Golgi-Tracker), and cholesterol-polyethylene glycol (PEG)_2k-fluorescein isothiocyanate (Chol-PEG-FITC) were adopted to visualize the nucleus, ER, mitochondrion, lysosome, Golgi apparatus, and plasma membrane, respectively. Scale bar: 10 μm. (d) Confocal images of Hoechst- and FITC-labeled γ-H2AX-stained A549 cells after various treatments as indicated. Scale bar: 10 μm. (b–d) Reprinted with permission from Reference [197]. Copyright 2018, American Chemical Society. (e) Scheme illustrating the use of siRNA/Zr-FeP MOF nanoshuttles for multimodal imaging and synergistic low-temperature PTT and PDT. Reprinted with permission from Reference [194]. Copyright 2018, Wiley-VCH.

Figure 8 (a) Scheme showing the use of TiH_1.924 nanodots (NDs) for SDT and PTT. Reprinted with permission from Reference [202]. Copyright 2020, Nature Publishing Group. (b) Scheme describing the use of Bi₂S₃ for mild PTT, and the use and working mechanism of BNN-Bi₂S₃ for combined NO-mediated gas therapy and mild PTT. Reprinted with permission from Reference [214]. Copyright 2019, Wiley-VCH. (c) Schematic illustration of DSP-mediated gene delivery and the photothermal activation of gene expression under NIR light irradiation. Reprinted with permission from Reference [217]. Copyright 2017, Wiley-VCH.

Figure 9 (a) Scheme illustrating the use of the IR820/aPD-L1-encapsulated LG depot for SMPAI. Reprinted with permission from Reference [256]. Copyright 2019, Nature Publishing Group. (b) Scheme depicting the fever-type photothermal treatment and Fenton reaction-enhanced immunotherapeutic effect by using the FeOOH@STA/Cu-LDH nanohybrid. Reprinted with permission from Reference [43]. Copyright 2020, Wiley-VCH.

Articles: Latest Articles; Most Read; Collections

Updates: Events; News; Multimedia

About: About Us

Contact

No. 86 Xueyuan South Road, Haidian District, Beijing

100081

010-62662699(Operation and Technical Support)

qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House