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Finely Tailored Conjugated Small Molecular Nanoparticles for Near-Infrared Biomedical Applications
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Xiaozhen Li1, *, Ruohan Zhang1, Yanlong Yang1, Wei Huang1, 2, 3, *
Research. Vol 8 Article ID 0534
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Research. Vol 8 Article ID 0534
• Review Article •
Finely Tailored Conjugated Small Molecular Nanoparticles for Near-Infrared Biomedical Applications
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Xiaozhen Li1, *, Ruohan Zhang1, Yanlong Yang1, Wei Huang1, 2, 3, *
Affiliations
  • 1 Frontiers Science Center for Flexible Electronics (FSCFE) & Institute of Flexible Electronics (IFE), Northwestern Polytechnical University, Xi'an 710072, P. R. China.
  • 2 Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Nanjing Tech University (Nanjing Tech), Nanjing 211816, P. R. China.
  • 3 State Key Laboratory of Organic Electronics and Information Displays and Jiangsu Key Laboratory of Biosensors, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, P. R. China.
Published: 2025-01-10 doi: 10.34133/research.0534
Outline
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Near-infrared (NIR) phototheranostics (PTs) show higher tissue penetration depth, signal-to-noise ratio, and better biosafety than PTs in the ultraviolet and visible regions. However, their further advancement is severely hindered by poor performances and short-wavelength absorptions/emissions of PT agents. Among reported PT agents, conjugated small molecular nanoparticles (CSMNs) prepared from D-A-typed photoactive conjugated small molecules (CSMs) have greatly mediated this deadlock by their high photostability, distinct chemical structure, tunable absorption, intrinsic multifunctionality, and favorable biocompatibility, which endows CSMNs with more possibilities in biological applications. This review aims to introduce the recent progress of CSMNs for NIR imaging, therapy, and synergistic PTs with a comprehensive summary of their molecular structures, structure types, and optical properties. Moreover, the working principles of CSMNs are illustrated from photophysical and photochemical mechanisms and light–tissue interactions. In addition, molecular engineering and nanomodulation approaches of CSMs are discussed, with an emphasis on strategies for improving performances and extending absorption and emission wavelengths to the NIR range. Furthermore, the in vivo investigation of CSMNs is illustrated with solid examples from imaging in different scenarios, therapy in 2 modes, and synergistic PTs in combinational functionalities. This review concludes with a brief conclusion, current challenges, and future outlook of CSMNs.

Xiaozhen Li, Ruohan Zhang, Yanlong Yang, Wei Huang. Finely Tailored Conjugated Small Molecular Nanoparticles for Near-Infrared Biomedical Applications[J]. Research, 2025 , 8 (1) : 0534 . DOI: 10.34133/research.0534
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Introduction
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Near-infrared (NIR) phototheranostics (PTs) have attracted considerable attention from researchers due to their timely monitoring of PT agents and precision therapy of disease in the NIR region [1–12]. Notably, NIR PTs have clarified their superiority over PTs in the ultraviolet (UV) and visible regions regarding tissue penetration depth, signal-to-noise ratio (SNR), and biosafety [4,13–16]. Three photo-diagnostic technologies are generally engaged, including fluorescence imaging (FLI), photoacoustic imaging (PAI), and Raman imaging (RI). NIR FLI can obtain a whole-body image, pinpointing the tumor location [17–23]. PAI utilizes NIR light to stimulate ultrasonic vibration, affording deep penetration and high temporal–spatial resolution [24–30]. RI is featured with a cell-silent region (1,800 to 2,800 cm−1), enabling zero-background imaging [31–33]. Phototherapy exploits photoenergy to produce hyperthermia and toxic reactive oxygen species (ROS) for photothermal therapy (PTT) and photodynamic therapy (PDT), respectively [1,34–44]. PDT and PTT have become quite popular owing to their attractive merits, such as noninvasiveness, minimal side effects, and high specificity [45–56]. Freely combining 3 photo-diagnostic technologies (FLI, PAI, and RI) and 2 photo-therapeutic modes (PTT and PDT) endows NIR PTs with more possibilities (Fig. 1) [57–60]. However, further advancement of NIR PTs critically lies in performance optimization and absorption/emission wavelength extension (over 650 nm) of PT agents.
Until now, 2 main categories of NIR PT agents, including inorganic and organic materials, have been reported [9,61–64]. Inorganic nanomaterials show excellent performance in NIR absorbance. However, they are always confronted with long-term toxicity concerns induced by the potential leakage of toxic heavy metal ions and minimal biodegradability, which limits their further clinical translations [65]. For instance, carbon nanotubes were added to the SIN (Substitute it Now) list as the first nanomaterials in 2019 [66]. In contrast, organic nanomaterials, including cyanine dyes, D-A-typed conjugated small molecular nanoparticles (CSMNs), and semiconducting polymeric nanoparticles (SPNs), are more preferred in biological applications because of their good biocompatibility, favorable optical properties, low dark toxicity, and tunable optical properties [48,67–70]. Among them, CSMNs possess higher photostability and tumor accumulation than cyanine dyes [such as Food and Drug Administration-approved indocyanine green (ICG)] [65,71] and more precise molecular structures and higher reliability than SPNs; thus, they have recently emerged as one attractive and promising candidate. The CSMNs are prepared with D-A-typed photoactive CSMs via a nanoprecipitation method or chemical modifications by hydrophilic molecules [such as polyethylene glycol (PEG), affibody, and peptide]. It is worth mentioning that the single photomolecule in CSMNs can achieve more than 1 to 4 functionalities, reflecting the intrinsic multifunctionality of CSMs in CSMNs [72,73]. Such advantages remove the concerns about higher cost and quality control induced by complicated fabrication and compositions.
Moreover, the molecular structures of CSMs are well defined, while their absorptions can be conveniently adjusted to the NIR region via rational structural design with high repeatability and reproducibility. By these attracting merits, the CSMNs have been applied in the detection of murine hepatoma H22 tumors and cell imaging [74], imaging of cytoplasm of cancer, location of mice bearing breast tumor [75], lymphatic imaging, brain tumor imaging, early-stage detection of head and neck cancers [71], hindlimb vasculature imaging, in-depth lymph node imaging [76], tumor blood vessels and targeted cancer imaging [77], imaging of traumatic brain injury [78], tumor discrimination [79], vein and artery identification [80], imaging of sentinel lymph nodes (SLNs) [81], deep brain tumor imaging [82], in vivo pH imaging [83], identification of tiny residual tumors and portrayal of the margin of tumors, guidance of surgery [84], PTT and PDT against tumor [65,85–89], and imaging (PAI, FLI, RI, or synergistic imaging)-guided tumor therapy (PTT, PDT, or combinational therapy) (Fig. 2) [72,84,90–98]. Therefore, a comprehensive and systematic review focusing on the progress of CSMNs is highly required to provide insights into its applications in both fundamental scientific research and clinical practice.
This review covers the recent development of CSMNs for NIR PTs (Fig 1). Their working principles are highlighted in terms of photophysical and photochemical mechanisms of CSMNs for imaging and therapy as well as light–tissue interactions toward biological applications (Fig. 5A to H). Chemical structures of CSMs and amphiphilic polymers for encapsulating CSMs are shown in Figs. 3 and 4, respectively. Structural types, optical properties, and applications of currently reported PT agents are summarized comprehensively in Tables 1 to 3. Moreover, molecular and nanoengineering strategies are discussed, with emphasis on improving performances and red-shifting absorption and emission spectra of CSMNs. Then, the biological applications of CSMNs are described from 3 aspects: (a) NIR imaging, including FLI, PAI, and RI in different scenarios; (b) NIR therapy, including PTT and PDT; and (c) synergistic NIR PTs, including dual-function, tri-function, and tetra-function CSMN-mediated NIR PTs. At last, a brief conclusion is given with a discussion of current challenges and possible outlook of CSMNs in the NIR PT field.
Working Mechanism
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The working mechanisms of CSMNs are illustrated from 2 perspectives. The first is the photophysical and photochemical mechanisms of CSMNs for FLI, PAI/PTT, RI, and PDT. Upon exposure to a laser, the molecules in CSMNs will firstly absorb incident light to be excited from the ground state (S0) to the excited singlet state (S1). As the Jablonski diagram shows, the excited molecules can dissipate energy via several pathways [99]. If the excited population dissipates their energy from S1 to S0 via the radiative decay, the molecules can emit fluorescence for FLI (Fig. 5A). If the excited population loses their energy from S1 to S0 via nonradiative decay, the molecules can release heat for PAI and PTT (Fig. 5B). If the excited population undergoes intersystem crossing (ISC) to triplet state (T1), there appear another 3 paths for excited molecules to release energy: (a) phosphorescence from T1 to S0; (b) energy transfer from T1 to surrounding O2 to produce 1O2; and (c) electron transfer from T1 to surrounding substrates to generate free radicals, such as O2·− and •OH. The produced 1O2 and free radicals (O2·− and •OH) can be used for type I and II PDT, respectively (Fig. 5D). For the Raman effect, the photons excite the molecule from S0 to a virtual energy state. When the excited molecules emit photons and return to a rotational or vibrating state different from S0, the energy difference between S0 and the new state causes the frequency of the emitted photons to differ from the wavelength of the excited light. If the molecules in the final vibrational state have a higher energy than the initial state, the excited photons have a lower frequency to ensure that the total energy of the system is maintained. This change in frequency is called the Stokes shift. If the final vibrational state of the molecule is lower in energy than the initial state, the excited photon frequency is higher, and this frequency change is called the anti-Stokes shift (Fig. 5C).
The second is light–tissue interactions toward biological application [100]. When the excitation light (usually a single light source) impinges on the surface of the objects of interest, a large portion of the incident light is reflected at the air/tissue interface due to the difference in refractive index between air and superficial tissue. The remaining incident light continuously penetrates the tissue and encounters scattering events, induced by the inhomogeneity of refractive exponents of different components of animal tissue (such as water, lipid membrane, and subcellular organelles). Scattering processes further weaken the signal for biological application and add background noise. Empirical measurements of scattering in tissues revealed an inversely proportional relationship between the scattering coefficient and wavelength (Fig. 5I), suggesting reduced scattering for all tissue types (including brain tissue, skin, cranial bone, mucous tissue, subcutaneous tissue, and muscle) at a longer wavelength. Endogenous chromophores such as deoxyhemoglobin and oxyhemoglobin show strong absorption in the <600-nm range (Fig. 5J). Except for UV–visible absorption from endogenous chromophores, water also displays a substantial contribution to the absorption spectrum of biological tissue with absorption maxima at 970, 1,200, 1,450, and beyond 1,800 nm, setting the boundaries of suitable optical windows for deep-tissue imaging. With consideration of the extinction spectra from all major light absorbers in biological tissue, the entire 700- to 1,700-nm spectral range (except a narrow water absorption centered at 1,450 nm) should permit deep-tissue imaging benefiting from low scattering and absorption of both incident and emissive photons. Autofluorescence from vital organs and bodily fluids is the fourth limiting factor for tissue penetration depth, which also decreases with the increase of detection wavelength but appears as a trailing tail to the NIR window and disappears beyond 1,500 nm (Fig. 5K). After the incident light encounters reflection, scattering, endogenous absorption, and autofluorescence, major photons will be absorbed by CSMs in CSMNs to be excited from S0 to S1 (virtual state for Raman scattering). According to different energy-dissipate pathways, including radiative decay, nonradiative decay, scattering, and ISC of CSMs, they can be used for FLI (Fig. 5E), PAI/PTT (Fig. 5F), RI (Fig. 5G), and PDT (Fig. 5H), respectively.
Strategies for Regulating the Absorptions of CSMs to the Second NIR Window (NIR-II)
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Because of the design difficulty, only a handful of CSMNs were reported for NIR-II PAI. To regulate the absorption of CSMs to NIR-II, several strategies, including increasing the number of thiophene bridges, building strong D-A-D conjugation, formation of J-aggregates, and molecular surgery, have been reported (Fig. 6).
Increasing the number of thiophene bridges
Ling's group [86] synthesized 3 D-A-D structured CSMs (CSM 14, CSM 14-1, and CSM 14-2) using triphenylamine (TPA) as the donor and benzo[1,2-c:4,5-c′]bis([1,2,5]thiadiazole) (BBT) as the acceptor, in which the number of thiophene bridges increased sequentially (0 to 2) (Fig. 6A). With the prolonged thiophene bridges, the absorption spectra extended from the first NIR window (NIR-I) to NIR, which might be attributed to the extension of the effective conjugation length of the molecular backbone. Notably, CSM 14-2 exhibited an absorption spectrum ranging from 700 to 1,200 nm, covering both NIR-I and NIR-II. Experimental results confirmed the feasibility and effectiveness of extending the optical absorption of CSMs into the NIR-II region by increasing the number of thiophene bridges in the molecular backbone.
Building strong D-A-D conjugation
Liu and colleagues [101] integrated a strong electron donor, 1,2-bis(4-N,N-dioctylaminophenyl)-1,2-diphenylmethane, into a difluoroboron-bridged azacyclic dimeric framework to design a CSM, BAF4, with a strong D-A-D conjugated system (Fig. 6B). Compared with the BAF4 analogs, BAF1 to BAF3 (with altered donor structure), BAF4's absorption peak red-shifted to 1,000 nm, with a maximum absorption wavelength exceeding 1,400 nm. Theoretical calculations further indicated the smallest energy gap of BAF4 containing strong electron-donating groups, theoretically supporting the design strategy. Thus, increasing the electron-donating ability of the donor to enhance the conjugation coupling of the main chain can significantly boost the NIR-II absorption of D-A-D structured small molecules.
Formation of J-aggregates
Feng's team [102] constructed an HBP/PTX nanoaggregate by self-assembling a cyclically fused azaBODIPY (referred to as HBP) with the hydrophobic paclitaxel (PTX) [102] (Fig. 6C). UV–visible–NIR absorption spectra showed that the absorption peak of HBP red-shifted from 878 to 1,012 nm, verifying the formation of J-aggregates. Thus, the successful construction of J-aggregates can also achieve a redshift of the absorption peak to NIR-II.
Molecular surgery
Lee and colleagues [85] designed a D-π-A-π-D CSM (CSM 13-1) using a twisted fluorene as the donor, BBT as the acceptor, and thiophene as the π-electron bridge for intramolecular charge transfer (ICT). Based on this, they performed substitution of the sulfur (S) atom in the BBT unit with selenium (Se) atoms, synthesizing structurally similar molecules CSM 13-2 and CSM 13 with different numbers of Se atoms (Fig. 6D). The absorption peaks of CSM 13-2 and CSM 13 both red-shifted to varying degrees compared to CSM 13-1. CSM 13 with 2 Se atoms showed an absorption peak at 1,060 nm. Via this molecular surgery of single-atom replacement, the absorptions of CSMs could be effectively regulated from NIR-I to NIR-II.
Imaging
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Imaging techniques provide wealthy physiological and pathological information of living subjects beneficial for precise disease diagnosis [100,103]. Among various imaging agents, CSMNs have recently attracted extensive research interest and have been explored as contrast agents in imaging [104]. In this part, the imaging applications of CSMNs, including FLI, PAI, and RI, will be investigated. Recently developed CSMNs for NIR imaging are summarized in Table 1.
Fluorescence imaging
As an emerging class of fluorescence probes, CSMNs have high fluorescence quantum yields (QYs) and structural reliability. Due to those charming merits, various CSMNs have been designed and explored for NIR FLI.
NIR-I FLI
In past decades, CSM-based fluorophores emitted fluorescence mainly in NIR-I (650 to 900 nm).
Detection of murine hepatoma H22 tumors and cell imaging. In 2012, Liu and colleagues [74] reported a bright fluorophore (CSM 1) with large 2-photon absorption (TPA) cross section and NIR emission for 1-photon and 2-photon imaging (Fig. 7A to C). To endow the molecule with good water solubility and cancer cell-targeting ability, CSM 1 was encapsulated into water-dispersible nanoparticles (CSMN 1, ~50 nm) with both DSPE-PEG2000 and DSPE-PEG5000-folate (Fig. 7A). One-photon in vivo FLI demonstrated that CSMN 1 could be effectively taken in by murine hepatoma H22 tumors with the assistance of folate-motivated active targeting effect and permeability and retention (EPR) effect. Two-photon cell imaging showed no autofluorescence from cells, and the ex vivo imaging achieved deep tumor imaging (~400 μm) (Fig. 7C). All results indicated the great potential of CSMN 1 for future imaging and diagnostic applications.
Imaging of cytoplasm of cancer and mice bearing breast tumor. More recently, our group presented a conjugated oligomer-based nanotherapeutic (CSMN 2) (Fig. 7D) with a high mass extinction coefficient of 93.5 l g−1 cm−1 and photoluminescence QY (PLQY) of 7.5% for high-performance cancer theranostics [75]. CSMN 2 showed broad absorption from 550 to 750 nm and a relatively narrow emission spectrum peaking at 760 nm (Fig. 7E). The cytoplasm of the cancer cell was delineated by red fluorescence from CSMN 2 (Fig. 7F), which demonstrated efficient endocytosis of CSMN 2. Moreover, CSMN 2 was applied for in vivo FLI, which exhibited maximum fluorescence signal in tumor location at 8 h after intravenous injection of CSMN 2 to mice bearing breast tumor (Fig. 7G). This in vivo imaging experiment thus guided the following cancer therapy.
NIR-II FLI
Compared with NIR-I fluorescence, fluorescence in NIR-II (1,000 to 1,700 nm) possesses deeper penetration depth and higher SNR because of reduced photoscattering and tissue autofluorescence [105–108]. Thus, recently, many efforts have been devoted to developing CSMs with NIR-II emission.
Lymphatic imaging, brain tumor imaging, early-stage detection of head and neck cancers, and imaging-guided removal of SLNs and squamous cell carcinoma. For instance, Dai et al. [71] synthesized an advanced small molecule (CSM 3) for NIR-II FLI. Before application, CSM 3 was modified with PEG to ensure its good water solubility and small size (Fig. 7H). CSM 3-PEG showed a small size of 3 nm and bright NIR-II fluorescence (QY: 0.3%) peaking at 1,055 nm (Fig. 7I). Pharmacokinetic experiments indicated that about 90% of CSM 3-PEG could be excreted from renal within 24 h after intravenous injection (Fig. 7J). First, CSM 3-PEG was used for lymphatic imaging. CSM 3-PEG mainly accumulated in the tumor, lymphatic vessel, and nodes, whereas most ICG entered the liver, the lymphatic vessel, and nodes, with only a weak signal in the tumor site (Fig. 7K). Moreover, compared with ICG, CSM 3-PEG with lower QYs showed a 2-fold enhancement in lymph node signal-to-background ratio (SBR). Even after 24-h injection of CSM 3-PEG, the tumor and SLN could be concurrently distinguished (Fig. 7L), which enabled selective removal of SLNs via surgical resection to prevent tumor metastasis. Second, CSM 3-PEG was applied for brain tumor imaging, in which brain tumors and vasculatures were visualized in high clarity by NIR-II imaging with CSM 3-PEG. By contrast, relatively low imaging quality was obtained by NIR-I imaging with ICG (Fig. 7M and N). At last, CSM 3 was modified with a small protein anti-epidermal growth factor receptor (EGFR) affibody (CSM 3-affibody) for early-stage detection of head and neck cancers in which EGFR was overexpressed (Fig. 7O). As expected, CSM 3-affibody showed great affinity to squamous cell carcinoma (SAS)-overexpressing EGFR in vitro imaging. The tumor-to-normal tissue ratio could reach ~15 within 6-h injection of CSM 3-affibody, 5 times higher than previously reported values. In vivo imaging further proved the specific targeting ability of CSM 3-affibody to SAS. Considering that CSM 3-affibody-mediated NIR-II imaging could clearly distinguish tumor and normal tissue (Fig. 7P), surgery was performed to remove the tumor site. After surgery, no NIR-II fluorescence signal could be detected from the mouse (Fig. 7Q), indicating the complete removal of SAS, which highlighted the superiority of CSM-mediated NIR-II FLI.
Imaging of hindlimb vasculature and lumbar lymph nodes. Based on this work, Chen's group [76] converted the carboxylic of CSM 3 to sulfonic acids (CSM 3-SA) (Fig. 8A) and found that CSM 3-SA in serum proteins (QY: 5%) displayed a 110-fold fluorescence increment than that in phosphate-buffered saline (PBS) (Fig. 8B), which was due to the formation of supramolecular assemblies between CSM 3-SA and serum proteins. With temperature increase, the fluorescence became much brighter with QY of 11% potentially derived from optimized interaction between CSM 3-SA and proteins. High-fidelity hindlimb vasculature imaging in the NIR-II window at the fastest frame rate so far was achieved with the CSM 3-SA/protein complex (Fig. 8C). Lumbar lymph node imaging further revealed the superiority of NIR-II imaging over NIR-I in deciphering deep anatomical information (Fig. 8D). This work brought hopes for developing NIR-II fluorophores with ultrahigh QYs.
Imaging of tumor blood vessels and targeted cancer imaging. Another new type of NIR-II fluorophore (CSM 4) with a different core structure from CSM 3 was designed first by Cheng's group [77], in which a thiophen spacer was introduced to the molecular backbone leading to an emission wavelength extension to ~1,400 nm (Fig. 8E). Based on CSM 4, 2 biocompatible probes (CSMN 4 and CSM-RM26) were constructed for NIR-II tumor blood vessels and targeted cancer FLI, respectively (Fig. 8F to H). This work expanded the diversity of NIR-II fluorophores adapting for various applications of NIR-II imaging technique.
Imaging of traumatic brain injury. To improve QYs of CSMs, Dai's group [78] utilized thiophene-based units as the donor and benzo[1,2-c:4,5-c′]bis([1,2,5]thiadiazole) (BBTD) as the acceptor to construct a new NIR-II fluorophore (CSM 5) with narrow-bandgap “D-A-D” structure, in which bulky 3,4-ethylenedioxy thiophene (EDOT) was introduced to avoid conjugated backbone interaction for further improving of the QYs. Moreover, CSM 5 was modified with PEG chains (CSM 5-PEG) to gain water solubility (Fig. 8I). As expected, CSM 5-PEG showed an emission peak at 1,071 nm and enhanced QYs of 0.70% in an aqueous solution (Fig. 8J). With these properties, CSM 5-PEG was applied for imaging of traumatic brain injury (Fig. 8K).
Tumor discrimination. Although CSMs have obtained initial success in NIR-II imaging, their QYs remain to be improved. Another work from Dai et al. [79] reported a shielding unit (S)–donor (D)–acceptor (A)–donor (D)–shielding unit (S) (S-D-A-D-S) structure to optimize the fluorescence performance for biological imaging. Specifically, BBTD was employed as the acceptor, EDOT/thiophen as the donor, and dialkyl fluorene/dibenzene as the shielding unit. According to this design guideline, 3 fluorophores (CSM 6, CSM 6-1, and CSM 6-2) were designed (Fig. 9A). The geometric, electronic, and optical properties of 3 molecular fluorophores are theoretically examined using density functional theory (DFT) and time-dependent density functional theory (TDDFT). Via PEGylation, water-soluble fluorophores (CSM 6-PEG, CSM 6-1-PEG, and CSM 6-2-PEG) showed red-shifted absorption in water, with peak absorption at 780, 828, and 741 nm (Fig. 9B), respectively. The QYs of CSM 6-PEG, CSM 6-1-PEG, and CSM 6-2-PEG were measured to be 2.0%, 0.02%, and 0.40% (Fig. 9C), respectively. The results confirmed that both the EDOT as the donor and dialkyl fluorene as the shielding unit accounted for the highest QY of CSM 6-PEG because they can protect the conjugated backbone from intermolecular and intramolecular interactions. CSM 6-PEG was thus applied for tumor discrimination (Fig. 9D).
Vein and artery identification. They also adopted a donor engineering strategy for further improving QYs, from which the relationship between the donor structure and QYs was illuminated [80]. The fluorophores all contain benzo[1,2-c:4,5-c′]bis[1,2,5]thiadiazole (BBTD) as acceptor, fluorene as shielding unit, and thiophen as the second donor; the only variable was the first donor connected to the acceptor (Fig. 9E). Results showed longer absorption wavelength due to the added thiophene for extended conjugation and the ultrahigh QY of 5.3% as octylthiophene was the first donor (CSM 7-PEG) (Fig. 9F and G). Given the highest QY, CSM 7-PEG was applied for ultrafast vasculature imaging, from which high-fidelity images were acquired (Fig. 9H). The vein and artery can be identified via principal components analysis of images from ultrafast video (Fig. 9I). This work demonstrated the effectively tunable optical properties of CSMs via molecular engineering to obtain suitable fluorophores for high-performance NIR-II imaging.
Photoacoustic imaging
PAI is a hybrid imaging technique combining optical excitation with ultrasonic detection. This working principle endows PAI with deep penetration depth and high spatial resolution because of dramatically reduced photon scattering [109,110].
NIR-I PAI
Most reported CSM-based photoacoustic (PA) contrasts work for NIR-I PAI, which have received intense attention due to their advantages of strong photostability, good light-capturing ability, high photothermal conversion efficiency (PCE), and good biocompatibility. By these merits, they have been applied for diverse bioimaging.
Real-time imaging of SLNs. For instance, Liu and colleagues [81] reported an oligomer (CSM 8) for real-time PA imaging of SLNs under 800-nm laser irradiation. Before application, CSM 8 was wrapped into nanoparticles (CSMN 8) with DSPE-PEG2000 via a nanoprecipitation method (Fig. 10A). The obtained nanoparticles showed good NIR absorption and strong PA signal (Fig. 10B and C). After intradermal injection, the PA signal in the SLN site peaked at 10 min and then gradually decreased, which persisted for 90 min, enabling long-time PA imaging of SLN (Fig. 10D). This work showed great promise of the oligomer nanoparticles for SLN real-time imaging.
Imaging of brain tumor. Another CSM (CSM 9) reported by Cheng's group [82] was used for PA imaging of deep brain tumor. CSM 9 was synthesized by utilization of the tertiary amine group as a donor and the diimide group as an acceptor to form a D-π-A structure. CSM 9 was then encapsulated into water-dispersible nanoparticles (CSMN 9) with DSPE-PEG5000 (Fig. 10E), with an absorption peak at 700 nm. CSMN 9 was for PA imaging of the brain tumor of mice. Results showed that the deeper tumor site could be detected over time after intravenous injection of CSMN 9 (Fig. 10F). Moreover, they revealed the relationship between nanoparticles' concentration and PAI depth (Fig. 10G), which indicated that high concentration led to lower PAI depth because most incident light was absorbed by nanoparticles on the surface so that only a little laser light could transmit to the deeper site. On the other hand, a relatively low concentration allowed more laser light to pass through the surface and reach the deeper location even though PA intensity was still weakened. This work not only developed an excellent PA contrast for achieving deep brain tumor imaging but also provided insights into improving deep PAI.
In vivo pH imaging. To further improve SNR and enhance PA intensity, Pu and colleagues [83] developed an activatable PA nanoprobe with amplified PA brightness for in vivo PH imaging, which was composed of a semiconducting oligomer (CSM 10) to emit PA signal and a dye (BODIPY, PH-BDP) to enhance PA intensity and sense PH (Fig. 10H). As PH-BDP had lower orbital energy than CSM 10, photoinduced electron transfer (PET) was favored to quench the fluorescence of CSM 10 and amplified its PA intensity. Moreover, PH-BDP possessed a hydroxy group that could be protonated under acid conditions, thus allowing pH sensing. Results showed that ratiometric PA intensity could be enhanced by about 3.1 times at different PH varying from 7.4 to 5.5 in vitro, which enabled estimation of in vivo PH (Fig. 10I to K). This work showed great potential for developing nanoprobes with high specificity and selectivity.
NIR-II PAI
Compared with NIR-I PAI, NIR-II PAI shows irreplaceable advantages including higher tissue penetration depth, SNR, and maximum permissible exposure (MPE) to laser [12]. However, due to the design difficulty, there is only a handful of CSMNs reported for NIR-II PAI. In PAI, the photothermal effect is naturally accompanied. For the illustration of NIR-II PAI, please refer to the first example of NIR-II PTT in the following part.
Raman imaging
RI, as a complementary optical imaging technique, is characterized by a bio-silent region (1,800 to 2,800 cm−1), in which no endogenous Raman signal can be detected, enabling background-free and precise imaging [31–33]. Thus, developing CSM-based nanoprobes with prominent Raman signals in the cell-silent region of Raman is of particular significance in the field of theranostics.
Identification of tiny residual tumors and the margin of tumors and guidance of surgery
For example, Tang and colleagues [84] recently reported an agent (CSM 11) with boosted fluorescence, photoacoustic, and Raman signature for accurate navigation of cancer surgery (Fig. 11A). CSM-based fluorescence and PAI have been well illustrated before, so only the Raman property of CSM 11 will be highlighted here. CSM 11 with large phenyl-alkyne-phenyl substituted units displayed strong Raman signals at 2,215 cm−1 (Fig. 11B) in the cell-mute region. It was endowed with good water solubility by being wrapped with DSPE-PEG2000 to form nanoparticles (CSMN 11). Raman signal detection results showed that the unit of phenyl-alkyne-phenyl in free molecules shows higher Raman intensity than that in aggregated molecules (Fig. 11B), which might be contributed to the active intramolecular motion of phenyl-alkyne-phenyl in free molecules. CSMN 11-mediated RI was successfully applied to identify tiny residual tumors and portray the margin of tumors with microscopic resolution and high SNR during surgery (Fig. 11C to E). With the accurate guidance of intraoperative imaging, the surgeon removed the residual tiny tumors (Fig. 11F to H). After the removal of weeny tumors, the survival rate of mice was significantly improved. Therefore, this work demonstrated the great potential of CSMN-mediated RI in inspecting tiny tumors.
Therapy
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CSMNs have been widely applied in tumor therapy, including PTT and PDT, because of their favorable biocompatibility, high photostability, design flexibility, and high photon-absorbing ability. During treatment, the CSMNs first absorb incident NIR light to be excited from S0 to S1. The excited CSMs in CSMNs dissipate energy via several pathways. If the CSMs decay back to S0 via nonradiative decay, local heat will be generated for PTT; if they undergo ISC to T1, it can transfer its energy to surrounding oxygen or electrons to surrounding substrates to generate ROS for PDT. Whether PTT or PDT, they possess many merits like noninvasiveness, good efficacy, easy manipulation, and high specificity [13,111,112]. Therefore, CSMN-mediated PTT or PDT holds promise for future clinical translation in cancer therapy. Recently developed CSMNs for NIR therapy are summarized in Table 2.
Photothermal therapy
High absorptivity and PCE are crucial for CSMNs to achieve efficient PTT [65,93]. Thus, many recent efforts have been devoted to developing and designing high-performance CSM-based NIR photothermal agents (PTAs).
NIR-I PTT
For example, our group reported an “A-D-A” structured oligomer (CSM 12) [65]. Before application, CSM 12 was transformed into water-soluble nanoparticles (CSMN 12), showing strong absorption at 808 nm and a high PCE of 82% (Fig. 12A to C). When exposed to 808-nm laser irradiation, CSMN 12 showed a fast temperature increment of around 45 °C within 5 min. After 10-cycle heating/cooling, there appeared little influence on the photothermal conversion ability of CSMN 12. The “A-D-A” structure and flexible intramolecular motion of D-A links were considered as the main reasons for the high PCE. Notably, CSMN 12 could be degraded in the bio-mimicking environment (Fig. 12D), removing the toxicity concern of CSMN 12 in living body. By strong mass extinction efficiency (123.4 l g−1 cm−1) and high PCE, CSMN 12 showed severe phototoxicity to 3 kinds of cell lines (A549, 4T1, and Hela cells). Most importantly, the tumors were thoroughly eliminated in antitumor experiments. This work thus presented an effective CSMN and paved an avenue for developing and exploring highly efficient CSMNs for PTs.
NIR-II PTT
Although CSMNs have received a lot of progress in NIR-I PTT, CSMN-mediated NIR-II PTT has rarely been reported because of the design difficulty of CSMs with strong absorption in the NIR-II region. Compared with NIR-I PTT, NIR-II light-initiated PTT has many advantages, such as deeper penetration depth resulting from low photon scattering and higher MPE (MPE for 1,064 nm is 1 W cm−2, while that for 808 nm is 0.33 W cm−2) [113,114]. Thus, developing and designing CSMN-based NIR-II PTT agents is highly desirable.
To achieve CSMN-mediated NIR-II PTT, our group delicately tuned the optical absorption of π-conjugated small molecules from the NIR-I window to the NIR-II window through molecular surgery of single-atom substitution (Fig. 12E) [85]. Via selenium (Se) atom introduction, an oligomer (CSM 13) with an absorption peak over 1,000 nm was first reported (Fig. 12F). After being encapsulated into nanoparticles (CSMN 13), it showed an unprecedently high PCE of 77% under 1,064-nm illumination (Fig. 12G). PA imaging showed that CSMN 13 with 1,064-nm laser irradiation showed deeper tissue penetration depth than CSMN 13-1 with 808-nm irradiation (Fig. 12H), revealing the superiority of CSMN 13 and 1,064-nm laser irradiation. Cell experiments showed that CSMN 13 could efficiently kill A549 and 4T1 cancer cells when exposed to a 1,064-nm laser. Under the guidance NIR-II PAI, in vivo PTT also achieved a satisfied curative effect, further demonstrating the excellent photothermal performance of CSMN 13. The biological evaluation indicated that CSMN 13 induced little side effects in the treated mice. Therefore, this work first realized the CSMN-mediated NIR-II PTT and offered an effective strategy for designing high-performance NIR-II CSMs.
Another kind of recently reported NIR-II small molecule for PTT application is from Ling's group [86]. In this work, 3 conjugated molecules (CSM 14-1, CSM 14-2, and CSM 14) with typical “D-A-D” structures were designed and synthesized by adopting a molecular engineering strategy (Fig. 12I). With an increasing number of thiophen bridges, the optical absorption of these CSMs was red-shifted (Fig. 12J). When 2 thiophen units were introduced (CSM 14), the absorption simultaneously covered NIR-I and NIR-II windows. CSM 14-1, CSM 14-2, and CSM 14 were then transformed into nanoparticles (CSMN 14-1, CSMN 14-2, and CSMN 14), showing respective PCE 25.3%, 31.5, and 31.6% under 1,064-nm laser irradiation. Moreover, CSMN 14 showed a higher extinction coefficient of 5.82 l g−1 cm−1 at 1,064 nm than CSMN 14-1 (without thiophen units, 1.31 l g−1 cm−1) and CSMN 14-2 (containing one thiophen units, 0.30 l g−1 cm−1). Given its good properties, CSMN 14 was selected for the next application. Results show that CSMN 14 could achieve deeper tissue PTT under 1,064-nm laser irradiation than 808 nm both in vitro and in vivo (Fig. 12K and M), indicating the superiority of NIR-II PTT. Under 1,064-nm laser irradiation, CSMN 14 showed a good tumor ablation effect in in vivo experiments (Fig. 12L). Collectively, this contribution developed a kind of novel CSMs while proposing a useful strategy for achieving CSM-based NIR-II PTT.
Photodynamic therapy
Most photosensitizers (PSs) possess relatively short excitation wavelengths (400 to 700 nm), which show the limitation of shallow tissue penetration depth, hindering their further bioapplication. NIR light-excited PSs can greatly address this problem and thus are expected to be promising PDT candidates. Unfortunately, it is well known that the design and synthesis of NIR-absorbing PSs are very difficult because of their notorious instability and high triplet electronic energy requirement. To achieve NIR PDT, our group adopted NIR 2-photon excited PSs for FLI and PDT (Fig. 13A and B) [87]. In this work, we reported a guideline for designing high-performance PSs and fluorophores by regulating ΔE ST and oscillator strength (f). By introducing electron donors with different electron-donating abilities, 2 synthesized molecules (CSM 15 and CSM 15-1) showed tunable ΔE ST and f. CSM 15 with small ΔE ST and f was beneficial for ROS generation (Fig. 13D), while CSM 15-1 with large ΔE ST was favorable for fluorescence emission (Fig. 13C). Under 2-photon irradiation (800 nm), the assembled CSM 15 (CSMN 15) showed a more efficient PDT effect (Fig. 13E) than CSMN 15-1. This study thus provided an effective strategy for designing and developing efficient fluorescent imaging and PDT agents.
Moreover, Tian and colleagues [88] recently reported an “A-D-A”-structured PS (CSM 16) with bright NIR-II emission for efficient type-I and type-II PDT (Fig. 13F). After assembling into nanoparticles (CSMN 16), CSM 16 showed NIR absorption ranging from 700 to 1,000 nm, and NIR-II fluorescence emission peaked at 1,035 nm with a high QY of 5.2% (Fig. 13G). The electron spin resonance (ESR) measurements confirmed the generation of ROS, including 1O2 and •OH by CSMN 16 (Fig. 13H). The ROS QY of CSMN 16 was calculated to be 2.7% with ICG as reference (0.2%). Because of the concurrent generation of 1O2 and •OH, CSMN 16 efficiently killed the cancer cells (>90%) both under normoxia and hypoxia after 880-nm laser irradiation (Fig. 13I). In vivo experiments also confirmed the high-performance PDT effect of CSMN 16. Therefore, this work showed great potential for accelerating the development of efficient hypoxia-resistant NIR PSs.
Another work reported by Chen's group [89] presented another “A-D-A”-typed PS (CSM 17) for combinational PDT and PTT (Fig. 13J to L). This designed PS showed suitable energy levels and intense ICT, enabling efficient dual-mode phototherapy. After assembling with the folate-functionalized copolymer, the prepared nanoparticles (CSMN 17) showed good biocompatibility, high photostability, 1O2 QY (18.6%), and PCE (36.5%), and active targetability to cancer cells. By these merits, CSMN 17 achieved good anticancer efficacy under 808-nm irradiation. This work thus revealed the great promise of “A-D-A”-structured single molecule as efficient PSs for NIR light-initiated dual phototherapy of tumors.
Synergistic PT
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Synergistic PTs that can simultaneously achieve diagnosis and therapy show obvious advantages by comparison with single imaging or therapy mode. With finely engineered structures and superior photophysical properties, CSMNs have received wide recent attention. The following will illustrate from 3 perspectives based on the functionalities of CSMNs: dual-function CSMNs, tri-function CSMNs, and tetra-function CSMNs. Recently developed CSMNs for NIR synergistic PTs are summarized in Table 3.
Dual-function CSMNs
PAI-guided PTT shows many charming merits, such as noninvasiveness, easy manipulation, minimal adverse effects, and high therapy outcomes [115,116]. PTT is naturally accompanied with PAI because the PA signal is from heat-generated acoustic waves [117,118]. Thus, CSMNs in PAI and PTT can exert a maximized imaging therapy effect simultaneously and will not compromise each other. Moreover, the photo-absorbing/sound release working principle enables the PAI technique to noninvasively probe deep-tissue information (5 to 7 cm) with high spatial resolution and contrast [75,119,120]. PTT possesses many advantages, such as noninvasiveness, good therapy effect, and easy manipulation [48,121]. Thereby, PAI/PTT is one of the most promising PT modes.
To overcome the problem of poor photostability, photobleaching, and intolerance to reactive oxygen/nitrogen species (RONS) of NIR-absorbing organic small molecules, Tang and coworkers [90] reported a small molecule (CSM 18)-based nanoparticles (CSMN 18) with intense NIR absorption within 700 to 900 nm for highly effective PTT under the guidance of PAI (Fig. 14A and B). Compared with the conventional cyanine, ICG, CSMN 18 showed much stronger thermal/photothermal stabilities and photobleaching/RONS resistances. These merits enabled CSMN 18 to significantly suppress tumor growth in vivo under the guidance of PAI. To boost the photothermal effect and PA signal of CSMs, another work from Tang's group [91] reported a concept of bond stretching vibration, a kind of molecular motion with high frequency and insensitive to external environmental restraint. As a proof of concept, 2 D-A structured compounds (CSM 19 and CSM 19-1) were synthesized. The only difference between these 2 molecules was that CSM 19-1 possessed 2 more phenyl groups than CSM 19, contributing to the increased bond stretching vibration in CSM 19-1 (Fig. 14C). By the increased vibration, CSMN 19-1 showed better performance than CSMN 19 regarding the PCE (59% versus 52%), PA signal generation, and PA imaging of tumors. This work thus provided a useful strategy to improve the photothermic and PA effect by utilizing intramolecular bond stretching vibration.
Although numerous PTAs have been developed in recent years, most employed synthetic methods require noble metal catalysts and high temperatures. To remove these concerns, our group reported a facile photochemical reaction for synthesizing organic PTAs with no need for noble metal catalysts and heating (Fig. 15A) [92]. Through this reaction, 2 CSMs (CSM 20-1 and CSM 20) with highly nonplanar structures were first designed and synthesized (Fig. 15B). The synthesized molecules were constructed with 2 same donors (Michler's base) and one acceptor (tricyanoquinodimethane), showing good optical absorption over 1,000 nm (Fig. 15C), remarkable NIR extinction coefficients, and excellent photothermal effect. The assembled nanoparticles (CSMN 20) showed good biocompatibility, excellent anti-photobleaching ability, and a high PCE of 75% (Fig. 15D). The excited state dynamic study further revealed the ultrafast nonradiative decay of the excited molecules in CSMN 20 (Fig. 15E). By these merits, CSMN 20 achieved high-resolution in vivo PAI (Fig. 15F) and high-efficiency photothermal tumor ablation (Fig. 15G). This work thus provided a useful approach as a supplementary to current methods for synthesizing effective CSM-based PTAs.
Reported CSMs typically possess low NIR absorbances. To boost the absorbance, our group reported a diradicaloid molecular structure (CSM 21) for highly effective PAI-guided PTT [93]. The intense charge transfer resulting from D-A interaction in CSM 21 led to an obvious diradical character (Fig. 15H), which was conducive to NIR absorption (Fig. 15I). CSM 21 possessed a much higher mass extinction coefficient of ~220 l/g/cm compared with those (~5 to 100 l/g/cm) of typical organic molecules. Assembled CSM 21 (CSMN 21) could resist long-time photoirradiation (Fig. 15J) and produce sufficient heat for PTT with a high PCE of 68%. Cell experiments showed that CSMN 21 achieved over 90% A549 cell fatality rate even at a relatively low concentration (6.25 μg/ml). In vivo anticancer experiments realized complete tumor ablation under the guidance of PAI (Fig. 15K). This work thus showed the great potential of developing diradicaloid molecules for improving NIR absorbance to facilitate biomedical applications. Except for this, other croconaine dyes have also been reported for NIR bioimaging and theranostics [122–124].
Tri-function CSMNs
NIR light-excited PTs are highly desirable because of their high penetration depth. However, their further development is greatly hindered by a limited number of PSs with long-wavelength absorption. To break this deadlock, our group reported a series of benzo[c]-thiophene (BT)-based molecules (CSM 22-1, CSM 22-2, and CSM 22) with tunable NIR absorption by modulating the electronic characters of donor and/or π subunits for multimodal PTs (Fig. 16A) [94]. Among these 3 molecules, CSM 22, with the maximum absorption peak at 802 nm, was prepared into nanoparticles (CSMN 22) (Fig. 16B). Remarkably, the ROS generation ability of CSMN 22 was 10.3-fold higher than ICG (Fig. 16C). Moreover, upon exposure to an 808-nm laser, CSMN 22 exhibited a good in vivo photoacoustic signal (Fig. 16D) and photothermal effect (Fig. 16E). With these merits, CSMN 22 achieved good PA imaging performance and dual-modal phototherapy effect.
Another small molecule (CSM 23) for PAI-guided PDT/PTT synergistic therapy (Fig. 16F) was reported by Dong and colleagues [95]. CSM 23 was synthesized by conjugating a typical donor of TPA to a diketopyrrolopyrrole (DPP) core, in which the thiophene group in DPP was used to increase the ISC ability via the heavy atom effect, while TPA was introduced for red shifting the absorption and enhancing the charge transport capacity. CSM 23 showed a maximum absorption peak at 630 nm, while the assembled nanoparticles (CSMN 23) showed a red-shifted and widened absorption peaking at 660 nm (Fig. 16G). Moreover, CSMN 23 showed a relatively high PCE of 34.5% and singlet oxygen (1O2) generation (Φ = 33.6%) upon exposure to 660-nm laser irradiation (Fig. 16H). These advantages allowed CSMN 23 to achieve excellent tumor-elimination ability via photothermal and photodynamic synergistic effect in living subjects even at a low dosage of 0.2 mg/kg under the guidance of PAI (Fig. 16I and J).
To overcome the existing problems, such as complicated architecture and unwanted side effects in current PTs, Fan and colleagues [96] reported a one-for-all nanoplatform (CSMN 24) with mitochondria-targeting ability based on the single molecule (CSM 24) for NIR-II FLI, PDT, and PTT (Fig. 17A). CSMN 24 was formed by encapsulating hydrophobic CSM 24 using amphiphilic TPP-PEG-PPG-PEG-TPP copolymer, in which TPP functioned as a mitochondria-targeting group. Upon exposure to an 808-nm laser, CSMN 24 showed a high QY of 2.2% in water, PCE of 39.6%, and Φ of 2.3% (12 times higher than ICG). Taking these merits together, CSMN 24 achieved efficient NIR-II FLI-guided mitochondria-targeting phototherapy against tumors.
Multi-modality imaging-guided cancer therapy combining precise diagnosis and efficient treatment has become a powerful PT platform. However, currently reported multifunctional systems usually comprised multicomponent and complicated structures, which retarded the progress of clinical translation. To simplify the multifunctional system, Sun et al. reported an effective small molecule (CSM 25) with an intrinsic multifunctionality for NIR-II FLI, PAI, and PTT (Fig. 17B) [97]. The assembled nanoparticles (CSMN 25) showed bright NIR-II fluorescence that peaked at 976 nm, strong PA signals in the tumor site, and a significant tumor inhibition effect, revealing the great potential of CSMN 25 as a PT platform.
Tetra-function CSMNs
Multifunctional PTs have recently attracted wide research interest due to their impressive synergetic effects [125–127]. However, current nanoplatforms, especially for those involving more than 3 functions, are confronted with their inherent drawbacks, such as complicated components and the requirement of multi-laser excitation, which severely hinder their further progress in clinical translation [50,84,95,128]. To solve these problems, Fan and colleagues [98] reported a single small molecule (CSM 26)-based multifunctional PT (CSMN 26), which could emit NIR-II fluorescence (0.52%), release toxic ROS (1O2 QY = 49.3%), and produce hyperthermia (PCE = 23%) upon exposure to single NIR laser (660 nm) irradiation. By these merits, CSMN 26 achieved good performance in NIR-II FLI, PAI, PTT, and PDT.
To integrate tetra-functions into one single molecule while balancing and maximizing the efficacy of each function, our group reported an A-D-A-structured small molecule (CSM 27) coupled with rigidness and flexibility to simultaneously achieve NIR-II FLI, PAI, PDT, and PTT (Fig. 18A to C) [72]. The assembled nanoparticles (CSMN 27) showed high NIR absorption ranging from 600 to 900 nm (Fig. 18D, left) and strong fluorescence from 900 to 1,200 nm under 808-nm laser excitation (Fig. 18D, right). CSMN 27 also displayed good singlet oxygen generation ability (3.2-fold higher than ICG) (Fig. 18E), excellent PCE (52.8%) (Fig. 18F), and high NIR-II QY (3.0%) (Fig. 18G) under 808-nm laser illumination. Such balanced functionality might be attributed to the rigid and flexible structures of CSM 27 to tactically manipulate the energy dissipation paths (nonradiative against radiative decay). Both in vitro and in vivo experiments demonstrated excellent therapeutic effects through photodynamic and photothermal synergistic therapy with the guidance of dual-mode NIR-II FLI and PAI. This work thus opened a new avenue for the design and development of single conjugated oligomer nanomaterials for versatile cancer nanomedicines.
Another example from Tang and coworkers [73] reported a simple but powerful one-for-all PTs based on aggregation-induced emission (AIE)-active fluorophores. In this work, 3 fluorophores (CSM 28-1, CSM 28-2, and CSM 28) were designed and constructed by introducing the TPA unit as donor, and/or thiophene segment as donor and π-bridge, as well as 1,3-bis(dicyanomethylidene)indane moiety as acceptor (Fig. 18H). The TPA unit not only functioned as molecular rotors, its propeller-like highly twisted conformation, but also maintained both heat generation and fluorescence, while the vigorous stretching vibrations of C≡N in 2 malononitrile-modified indanes provided extra intramolecular motion in the aggregate state. The thiophene unit in CSM 28-2 and CSM 28 was for red-shifting the absorption/emission wavelength. Such structural features endowed the AIE molecule-based nanoparticles (CSMN 28-1, CSMN 28-2, and CSMN 28) with bright NIR-II fluorescence, efficient ROS production, and significant temperature increases under 660-nm laser irradiation. Among these 3 molecules, CSMN 28 showed strong NIR fluorescence, with almost half of the emission spectrum falling in the NIR-II region (over 1,000 nm), high PCE of 46.0%, and superior ROS generation efficiency. With these merits, CSMN 28 achieved effective PAI and NIR-II FLI-guided photothermal and photodynamic synergistic therapy with only a single injection and irradiation in living mice (Fig. 18I and J). This work provided new perspectives for the design and development of versatile cancer PT.
Conclusion and Outlook
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NIR PTs, combining timely diagnosis and precise therapy in the NIR region, have attracted more and more recent attention. Compared with PTs in the UV and visible regions, NIR PTs display higher tissue penetration depth, SNR, and better biocompatibility. NIR PT agents are usually inorganic or organic. Inorganic agents are always confronted with potential biotoxicity induced by heavy metal ions and nonbiodegradability, while organic agents successfully escape these problems by their potential biodegradability, favorable optical properties, and low dark toxicity. CSMNs prepared with D-A-typed photoactive CSMs show higher photostability and tumor accumulation than cyanine dyes and more accurate molecular structures and higher reliability than SPNs. Via rational structural design, CSMs can satisfy specific requirements of NIR PTs. Such design flexibility of CSMs has permitted CSMNs to achieve more possibilities in biological applications, such as imaging (cells, tumors, lymphatic, lymph nodes, brain tumors, hindlimb vasculature, PH, vein and artery, and surgery guidance), therapy (PTT and PDT), and synergistic PTs (dual-function, tri-function, and tetra-function PTs). To exert functions, CSMNs always involve 2 mechanisms. The first one is closely connected with the Jablonski diagram, while the second one is dependent on light–tissue interactions. Except for the illustration of 2 working mechanisms, strategies for improving performances and red-shifting absorption and emission spectra of CSMNs are also highlighted.
Despite rapid development, some challenges remain in the field of CSMN-mediated NIR PTs to address. The visible or NIR-I light hardly irradiates NIR PT agents in tumors or infections in deep tissues because of limited penetration depth (several centimeters depending on tissues) [129]. As Nikola Tesla said: “If you want to know the secrets of the universe, think in terms of energy, frequency, and vibration.” Thus, developing NIR-II light-responsive CSMNs is an effective method to improve tissue penetration depth attributed to its lower photoscattering and higher MPE (MPE for 1,064 nm is 1 W cm−2, while that for 808 nm is 0.33 W cm−2). As aforementioned, our group first delicately tuned the optical absorption of π-conjugated small molecules from the NIR-I window to the NIR-II window through molecular surgery of single-atom substitution [85]. Besides, to further boost the penetration depth, other tissue penetration energy, such as ultrasound and x-ray, should be explored to irradiate CSMNs. Specifically, ultrasound, a nonionizing radiation with no known risk, has been widely applied in imaging in clinics, which can pass through 3- to 5-cm-deep tissues at a frequency of 1 MHz [130]. On the other hand, x-ray is a high-energy radiation potentially used as a good signal inducer because of its deep-tissue penetration (the whole body) and well-established application technology [131]. As reported, organic luminophores emitting NIR afterglow and producing 1O2 have realized effective cancer theranostics after x-ray irradiation [132]. Moreover, organic phosphorescent nanoscintillator have achieved low-dose x-ray-induced PDT [133]. Thus, introducing ultrasound and x-ray as tissue penetration energy to CSMNs is innovative but dependent on rational molecule design.
The performances of CSMNs, involving their absorption, fluorescence emission, photothermal conversion,1O2 generation, and in vitro and in vivo PT efficacies, can be evaluated by extinction coefficients (𝜺), fluorescence QYs (Φf), PCE, 1O2 QYs (Φ), cell viabilities, and tumor volume–time curves, respectively. According to the summarized information in Tables 1 to 3, the absorption, excitation, and emission wavelengths of CSMNs and CSM-PEG range from 300 to 1,100 nm, 660 to 800 nm, and 600 to 1,200 nm, respectively. Their PCE, Φf, and Φ locate within 21.8% and 82%, 0.2% and 5.3% (NIR-II, in water), and 0.61% and 33.6%, separately. Remarkably, there is much room for CSMNs to improve regarding NIR-II FL QYs and 1O2 QY. To overcome this challenge, the PT agents should maximize their absorption upon exposure to a laser. Moreover, their energy dissipation paths, including nonradiative decay, radiative decay, and ISC, should be manipulated tactically via rational molecular design. Most importantly, the performances of CSMs should cater to clinical requirements.
Currently reported structure types include D-A-D, A-D-A, S-D-A-D-S, D-π-A, D-π-A-π-D, D-A, DD-A-DD, and D-π-π-A. By arranging electron donors and acceptors rationally, the CSMs can be equipped with the desired properties to achieve effective NIR PTs. It should be mentioned that only 2 categories of CSMs with similar acceptors have been reported for NIR-II PAI and PTT, which is owing to the design difficulty of CSMs with strong absorption in the NIR-II region. Particularly, most CSMs utilize electron-deficient benzo[1,2-c:4,5-c0]bis([1,2,5]thiadiazole) (BBTD) as their acceptor because of its strong electron-withdrawing ability. With the introduction of different donors, various molecules can be designed and synthesized for different purposes. In this review, enhancing the performance and shifting the absorption and emission spectra to longer wavelengths are key problems to address, closely dependent on effective molecular engineering and nanomodulation strategy.
Light-responsive CSMNs are well elaborated in this review. However, except for light, another external stimulus (such as ultrasound, x-ray, magnet, electricity, and heat as supplementary powerful energy sources)-responsive CSMNs should be further exploited to widen the applications of CSMNs. Besides, internal stimuli (such as redox, enzyme, PH, and temperature) should be taken into consideration when designing smart CSMs, which could diversify the applications of CSMNs.
Biosafety problems are closely associated with clinic translation. Exploring, developing, and designing biodegradable or renal-clearable CSMs are effective strategies to improve biosafety. Moreover, encapsulating CSMs with amphiphilic polymers (such as DSPE-PEG2000, DSPE-PEG5000-folate, DSPE-PEG5000, PEG-b-PPG-b-PEG, PS-b-PEG, and TPP-PEG-PPG-PEG-TPP) or modifying CSMs with hydrophilic molecules is a commonly used method to endow CSMs with good water solubility, targetability, and biocompatibility.
Currently, most reported CSMNs are applied at only the level of small animals such as mice. Applying them to large animals or nonhuman primates would be beneficial to accelerate their clinical translation. However, the development of experiments in nonhuman primates and the translation of these experiments to clinical human experiments face many challenges, such as the following: (a) The differences in body structure and internal circulation between nonhuman primates and small animals, and whether the experimental results in mice can achieve the same effect in nonhuman primates. (b) High cost: Nonhuman primates used for preclinical experiments are usually expensive, and there are financial limitations in using nonhuman primates for experiments before the perfect effect of the CSMNs is realized. (c) Safety regulation: The clinical transformation of CSMNs usually needs to invest a lot of work in the early stage to explore their possible toxic side effects and their impact on the human body. The small animal experiments are not enough to fully reflect the toxic side effects of CSMNs entering the human body. With rapid progress in chemistry, material science, photonics, nanotechnology, and nanomedicine, these challenges will be readily resolved in the coming future.
Funding
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  • Research Start-up Funds of Northwestern Polytechnical University(23GH02025)
  • Postdoctoral Innovative Talent Support Program(W016336)
  • Fundamental Science Center Foundation of China(D5110220297)
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Article Info
doi: 10.34133/research.0534
  • Receive Date：2024-08-29
  • Online Date：2025-07-23
  • Published：2025-01-10
Article Data
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History
  • Received：2024-08-29
  • Revised：2024-10-20
  • Accepted：2024-10-26
Funding
Research Start-up Funds of Northwestern Polytechnical University(23GH02025)
Postdoctoral Innovative Talent Support Program(W016336)
Fundamental Science Center Foundation of China(D5110220297)
Affiliations
    1 Frontiers Science Center for Flexible Electronics (FSCFE) & Institute of Flexible Electronics (IFE), Northwestern Polytechnical University, Xi'an 710072, P. R. China.
    2 Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Nanjing Tech University (Nanjing Tech), Nanjing 211816, P. R. China.
    3 State Key Laboratory of Organic Electronics and Information Displays and Jiangsu Key Laboratory of Biosensors, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, P. R. China.

Corresponding:

* Address correspondence to: (X.L.); (W.H.)
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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
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