Latest ArticlesThe antioxidant and immune-suppressive microenvironment of tumors has severely limited the efficacy of photodynamic therapy (PDT). To overcome these limitations, we proposed a novel nanoparticle (PEG-PFc/Hyp) that combined hypericin (Hyp) and ferrocene for synergistic anti-tumor therapy within a single system. Briefly, the optimum PEG114-PLL10 was reacted with ferrocene by the carboxylic acid N-succinimidyl ester(ferrocene-NHS), and the subsequent Hyp encapsulated in the above fabricated amphiphilic polymer. When under light irradiation, Hyp generated abundant reactive oxygen species (ROS) that synergized with •OH produced by ferrocene, leading to disrupted redox balance, amplified lethal lipid peroxidation (LPO) and inducing significant ferroptosis. Furthermore, the ferrocene could greatly alleviate hypoxia via O2 production, thereby cascaded enhancing the ROS production efficiency of PDT. As a result, the cascade augmented ROS level, alongside the glutathione (GSH) depletion in tumor cells, caused effective immunogenic cell death (ICD) and potent anti-tumor response. It turned out that the PDT-ferroptosis-ICD strategy enabled significant oxidative damage and tumor cell immunogenicity, offering great potential in cancer immunotherapy.
Copper dysregulation is a critical factor in tumorigenesis and cancer therapy, underscoring the need for in vivo Cu(Ⅰ) imaging in tumors to elucidate its pathological roles. However, developing molecular probes for high-sensitivity and high-resolution in vivo Cu(Ⅰ) imaging remains a significant challenge. Herein, we report a covalently targeted small-molecule probe for dual-modality fluorescence and photoacoustic (PA) imaging of Cu(Ⅰ) in tumors. This probe exhibits highly selective near-infrared fluorescence enhancement and a ratiometric PA response upon coordination with Cu(Ⅰ). Furthermore, it enables precise tumor targeting and sustained imaging through specific recognition and covalent anchoring to the neutral cholesterol ester hydrolase 1 (NCEH1) protein. In vivo experiments demonstrate its capability for dynamic tracking of Cu(Ⅰ) in tumors with high sensitivity via fluorescence imaging and micro resolution via ratiometric PA imaging. We anticipate this Cu(Ⅰ)-responsive dual-modality probe with targeted anchoring capabilities will be a powerful tool for investigating Cu(Ⅰ) dynamics and transport in tumors, thereby deepening our understanding of pathological roles of Cu(Ⅰ) in cancer biology.
Excessive and prolonged inflammatory monocyte activity accelerates left ventricular remodeling after myocardial infarction (MI). After myocardial reperfusion, the CCL2/CCR2 axis is considered to be a key chemokine axis that initiates and modulates tissue inflammatory damage. Effectively blocking the CCL2/CCR2 axis can reduce the chemotaxis of inflammatory monocytes to the infarct area, which has important therapeutic value for the repair of myocardium after reperfusion injury (MI/R). Here, we propose a nanoparticle carrying CCL2 silencing short interfering RNA (siRNA), which is prepared by coating a lipid hybrid CCR2-overexprssion macrophage cell membrane on a siRNA-loaded mesoporous silica nanoparticle. The overexpression of CCR2 and adhesion factors on the macrophage membrane improves its targeting ability, directing nanoparticle to the myocardial infarction area of MI/R-induced mice, the overexpress CCR2 in the macrophage cell membrane also adsorb more CCL2. Then by fusing with the cell membrane, siRNA is released into the injured endothelial cells cytoplasm, silencing the expression of CCL2. In vivo administration of the formula blocked CCL2/CCR2 axis, reduce the chemotaxis of inflammatory cells, regulate the immune microenvironment, further decreasing myocardial infarction area and improving cardiac function. Targeted block of CCL2/CCR2 axis represent a new therapeutic intervention for inflammatory disease.
Cerium oxide nanozymes (CeO2 NZs) exhibit enzyme mimetic activities and great promise for biomedical applications by mediating the dynamic cycling between Ce3+ and Ce4+. However, traditional preparation methods are often expensive and detrimental to the environment. Meanwhile, the problems of easy agglomeration, poor targeting and weak biocompatibility need to be solved. The available literatures have mainly reviewed CeO2 NZs in terms of its material properties, mechanisms and potential clinical applications. The literatures on the limitations of CeO2 NZs and the corresponding improvement methods are fragmented. Consequently, the limitations of CeO2 NZs and the strategies involving green preparation technology and modification mainly summarized, while the biosafety of the modification strategies are compared. Meanwhile, representative studies of potential clinical applications of CeO2 NZs over the past three years are outlined, along with a summary of their clinical translational prospects and challenges. Finally, the challenges of CeO2 NZs promotion technology are discussed.
Among various smart drug delivery systems (DDSs), redox-responsive systems have emerged as promising platforms for tumor therapy. Herein, we successfully fabricated a tumor microenvironment dual redox-responsive nanoparticle platform (DTX@Cys-0E NPs) assembled from an L-cystine-based biodegradable polymer (Cys-0E) for efficient delivery of docetaxel (DTX). The engineered Cys-0E features a unique structure containing both disulfide bonds and peroxalate ester bonds, synthesized via a one-step reaction. Notably, the strategic incorporation of 6-o-palmitoyl ascorbic acid (PA) not only enhances the stability of DTX@Cys-0E NPs but also generates tumor-specific H2O2. This PA-mediated H2O2 production triggers the degradation of the peroxalate ester bond, followed by CO2 generation, which ultimately results in DTX-controlled release. Simultaneously, the disulfide bonds in Cys-0E react with high concentrations of glutathione (GSH) in tumor cells, increasing the reactive oxygen species (ROS) level, and further facilitating drug release. Both in vitro and in vivo experiment results show that, once DTX@Cys-0E NPs are enriched into tumor cells, the rapid degradation of Cys-0E triggered by these stimuli leads to a burst release of DTX, inducing tumor cell apoptosis and exhibiting significantly better tumor inhibition compared to free DTX. In summary, this novel dual redox-responsive nano platform holds great promise as a controlled drug release system for cancer therapy.
Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO), has emerged as a promising therapeutic strategy for cancer. However, challenges such as uncontrolled iron delivery, insufficient ferroptosis induction efficiency, and off-target drug leakage limit its applications. To address these limitations, we developed a biomimetic nanoplatform (Fe-DTX@M) integrating cancer cell membrane-camouflaged Fe-based metallacycles with the chemotherapeutic drug docetaxel (DTX), which synergistically amplifies ferroptosis and apoptosis for precise and effective cervical cancer therapy. The membrane camouflage enabled highly efficient tumor-specific accumulation, achieving a 5.4-fold increase compared to non-targeted controls, and reduced systemic toxicity. Within tumors, Fe2+/Fe3+ cycles attributed to Fe-based metallacycle drove Fenton reactions to convert H2O2 into •OH, inducing LPO, while Fe3+-mediated glutathione depletion inhibited GPX4, amplifying ferroptosis with 2.4-fold malondialdehyde (MDA) increase. Acid-triggered DTX release of nanoplatform further promoted apoptosis, thereby enhancing therapeutic efficacy. Furthermore, Fe-DTX@M exhibited excellent long-term biocompatibility and safety in normal mice over 30 days post-intravenous injection. This combination of biomimetic metallacycles-induced ferroptosis and chemotherapy-induced apoptosis may provide a new paradigm for achieving effective cancer therapy.
Prodrug nanoassemblies (NPs) have attracted much attention in improving the selectivity of chemotherapy drugs, while most of them suffer from poor targeting efficiency. Biotin, a well-known tumor-targeting ligand, can greatly enhance tumor accumulation. Herein, we construct the biotinylated prodrug (Biotin-PTX) by connecting paclitaxel (PTX) to biotin via a disulfide bond, enabling the prodrug to self-assemble into nanoparticles (Biotin-PTX NPs). However, the pure NPs are observed to be rapidly cleared without polyethylene glycol (PEG) modifying, while excessive PEG can compromise their targeting efficiency, suggesting that it is crucial to optimize the amount of PEG. On this basis, the effect of distearoyl phosphatidylethanolamine-polyethylene glycol2000 (DSPE-PEG2k) ratios (0%, 5%, 10%, 20%, 40% and 60%, WPEG/Wprodrug+PEG) on their performance have been investigated. The results provide evidence that Biotin-PTX NPs containing 20% DSPE-PEG2k (20% NPs) can significantly improve colloidal stability and tumor-targeting efficiency. Moreover, 20% NPs exhibits good antitumor efficacy and safety compared with Taxol, Abraxane and Prodrug Sol. This work highlights the key role of moderate PEGylation in regulating the therapeutic performance of targeting NPs, offering a new way of thinking for tumor-targeting treatment.
With growing emphasis on drug efficacy, safety, and adverse reactions, many traditional Chinese medicines and their active ingredients, as well as compounds such as antibiotics, immunosuppressants, and hormones often face limited efficacy or give rise to adverse effects during application. To improve therapeutic outcomes and reduce systemic side effects, oral targeted drug delivery systems have become an important research direction. Hydrogels have shown great potential in the field of oral delivery to treat many diseases due to their superior drug protection ability and excellent biocompatibility. This review explores the physiological characteristics of the gastrointestinal tract and the significant advantages of oral hydrogels in drug delivery, and systematically introduces hydrogel carrier design strategies through physical crosslinking, chemical crosslinking, small molecule self-assembly, and metal ion coordination. Furthermore, it emphasizes recent advances in intelligent oral hydrogels and drug loading strategy. Lastly, the review summarizes the innovative applications of oral hydrogels in the treatment of diseases such as esophagitis, GI disorders, metabolic and endocrine diseases, osteoporosis, detoxification, and cardiovascular diseases, offering valuable insights and guidance for optimizing and advancing hydrogel-based drug delivery systems.
Age-related macular degeneration (AMD) represents a primary cause of vision loss in the elderly population. Reactive oxygen species (ROS) generation constitutes a pivotal pathogenesis mechanism in AMD. Berberine (BBR) shows therapeutic potential for dry AMD through its ability to mitigate cellular senescence and oxidative stress. However, BBR’s low transmembrane permeability severely limits corneal penetration via topic administration, creating an urgent need for novel posterior segment delivery strategies. In this study, we employed biocompatible ionic liquids (ILs) to enhance BBR permeation for posterior AMD treatment. Our approach features ocular surface pretreatment with ILs followed by topical administration of BBR solution. Comprehensive in vitro and in vivo safety assessments confirmed the biocompatibility of monoethanolamine-based IL (Mea-ILs) as ocular penetration enhancers. Trans-monolayer experiments using human corneal epithelial cells (HCECs) demonstrated that ILs enhance paracellular permeability, potentially through tight junction modulation. In vivo studies utilizing a sodium iodate-induced dry AMD mouse model revealed that pretreatment with the [monoethanolamine][citric acid] ([Mea][Ci]) IL significantly potentiated BBR's therapeutic efficacy. These findings not only expand pharmaceutical applications of ILs but also establish a safe, efficient strategy for noninvasive dry AMD therapy with BBR. Furthermore, this work provides critical insights for developing advanced penetration enhancers for posterior ocular drug delivery.
Acute respiratory distress syndrome (ARDS) is one of the diseases with a significant mortality rate due to respiratory failure. Yet, malignant microenvironment (MM) composed mainly of inflammatory cytokines (IC) and reactive oxygen species (ROS) limit the therapeutic effect. Herein we construct the nanoparticles (NPs) BSA-MnO2@Tan-IIA/PSLs (BMTPLs) to disrupt the vicious cycle between IC and ROS by suppressing IC production and scavenging ROS, which effectively remodels the MM of ARDS. The BMTPLs composed of the water-dispersible BSA-MnO2 (BM) and phosphatidylserine (PS)-consisting lipid shell containing lipophilic tanshinone IIA (Tan-IIA). After phagocytosed by activated macrophages (M1) in an efferocytosis-like manner originating from the PS effect, the released Tan-IIA inhibit NF-κB pathway and further suppresses the secretion of IC. Concurrently, BM scavenging ROS alleviates the oxidative stress microenvironment, which deeply enhances the anti-inflammation effect of Tan-IIA. Moreover, the low-level ROS and down-regulation IC promote the transformation from pro-inflammatory M1 to anti-inflammatory M2 contributing to restoring tissue homeostasis. The results in vitro and in vivo indicate that the MM of ARDS can be effectively remodeled by BMTPLs, which holds great potential for ARDS treatment.
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