An Ultrasmall SnFe2O4 Nanozyme with Endogenous Oxygen Generation and Glutathione Depletion for Synergistic Cancer Therapy

The tumor microenvironment (TME) with the characteristics of severe hypoxia, overexpressed glutathione (GSH), and high levels of hydrogen peroxide (H₂O₂) dramatically limits the antitumor efficiency by monotherapy. Herein, a novel TME-modulated nanozyme employing tin ferrite (SnFe₂O₄, abbreviated as SFO) is presented for simultaneous photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT). The as-fabricated SFO nanozyme demonstrates both catalase-like and GSH peroxidase-like activities. In the TME, the activation of H₂O₂ leads to the generation of hydroxyl radicals (•OH) in situ for CDT and the consumption of GSH to relieve antioxidant capability of the tumors. Meanwhile, the nanozyme can catalyze H₂O₂ to generate oxygen to meliorate the tumor hypoxia, which is beneficial to achieve better PDT. Furthermore, the SFO nanozyme irradiated with 808 nm laser displays a prominent phototherapeutic effect on account of the enhanced photothermal conversion efficiency (η  = 42.3%) and highly toxic free radical production performance. This “all in one” nanozyme integrated with multiple treatment modalities, computed tomography, and magnetic resonance imaging properties, and persistent modulation of TME exhibits excellent tumor theranostic performance. This strategy may provide a new dimension for the design of other TME-based anticancer strategies.     

Dual Enzyme Mimics Based on Metal–Ligand Cross-Linking Strategy for Accelerating Ascorbate Oxidation and Enhancing Tumor Therapy

The development of high-efficiency nanozymes is of great significance in the field of nanozymology, because this is one of the prerequisites for the sophisticated performance of nanozymes. Herein, the developed metal–ligand cross-linking strategy engineers porous carbon nanorod supported ultra-small iron carbide nanoparticles that possess excellent oxidase-like and peroxidase-like enzyme activities. The fabricated nanozyme can efficiently accelerate the oxidation of ascorbate (AA) to enhance cancer cells ablation efficacy. Due to the nanozyme having great surface atoms utilization ratio and large specific surface area, the AA can be rapidly and completely autoxidized within 20 min. Mechanism research demonstrates that the nanozyme's first activation of O₂ to generate superoxide free radicals (O₂^•−) via the oxidase-like pathway, then the O₂^•− directly oxidizes AA and produces hydrogen peroxide (H₂O₂). Simultaneously, the H₂O₂ transforms into the toxic hydroxyl radical through the peroxidase-like pathway and induces tumor cell death. Further in vitro and in vivo assays show the significant enhancement of the anti-tumor efficacy through AA oxidation which is catalyzed by the developed nanozyme. It is expected that this work will benefit not only the development of other efficient nanozymes, but also future advances in the field of AA oxidation induced tumor therapy.     

Glutathione‐Activatable and O2/Mn2+‐Evolving Nanocomposite for Highly Efficient and Selective Photodynamic and Gene‐Silencing Dual Therapy

Photodynamic therapy (PDT) has been applied in cancer treatment by converting O₂ into reactive singlet oxygen (¹O₂) to kill cancer cells. However, the effectiveness of PDT is limited by the fact that tumor hypoxia causes an inadequate O₂ supply, and the overexpressed glutathione (GSH) in cancer cells consumes reactive oxygen species. Herein, a multifunctional hybrid system is developed for selective and highly efficient PDT as well as gene‐silencing therapy using a novel GSH‐activatable and O₂/Mn²⁺‐evolving nanocomposite (GAOME NC). This system consists of honeycomb MnO₂ (hMnO₂) nanocarrier loaded with catalase, Ce6, and DNAzyme with folate label, which can specifically deliver payloads into cancer cells. Once endocytosed, hMnO₂ carriers are reduced by the overexpressed GSH to Mn²⁺ ions, resulting in the reduction of GSH level and disintegration of GAOME NC. The released catalases then trigger the breakdown of endogenous H₂O₂ to generate O₂, which is converted by the excited Ce6 into ¹O₂. The self‐sufficiency of O₂ and consumption of GSH effectively enhance the PDT efficacy. Moreover, DNAzyme is freed for gene silencing in the presence of self‐generated Mn²⁺ ions as cofactors. The rational synergy of enhanced PDT and gene‐silencing therapy remarkably improve the in vitro and in vivo therapeutic efficacy of cancers.     

Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 Nanoparticles to Enhance Photodynamic Therapy

Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO₂) nanoparticles toward endogenous hydrogen peroxide (H₂O₂) within the tumor microenvironment to generate O₂, multifunctional chlorine e6 (Ce6) loaded MnO₂ nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO₂‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO₂‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O₂ level benefited from the reaction between MnO₂ and H₂O₂, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO₂‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO₂‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.     

Self-Reliant Nanomedicine with Long-Lasting Glutathione Depletion Ability Disrupts Adaptive Redox Homeostasis and Suppresses Cancer Stem Cells

Bulk cancer cells and cancer stem cells (CSCs) harbor efficient and adaptive redox systems to help them resist oxidative insults arising from diverse therapeutic modalities. Herein, a tumor microenvironment (TME)-activatable nano-modulator capable of disrupting adaptive redox homeostasis, prepared by integrating FDA-approved xCT inhibitor sulfasalazine (SSZ) into pH-responsive hydroxyethyl starch-doxorubicin conjugate stabilized copper peroxide nanoparticles (HSCPs) is reported. Compared to poly(vinylpyrrolidone) (PVP)-stabilized copper peroxide nanoparticles, HSCPs exhibit superior physiological stability, longer circulation half-life, and higher tumor enrichment. Under an acidic TME, the active components inside HSCPs are productively released along with the disintegration of HSCPs. The specifically generated hydrogen peroxide (H₂O₂) from copper peroxide nanoparticles furnishes a constant power source for copper-mediated hydroxyl radical (•OH) production, serving as a wealthy supplier for oxidative stress. Meanwhile, the tumor-specific release of Cu²⁺ and SSZ can induce long-lasting glutathione (GSH) depletion via copper-mediated self-cycling valence transitions and SSZ-blocked GSH biosynthesis, thereby reducing the offsetting action of the antioxidant GSH against oxidative stress. As a result, this sustained oxidative stress potently restrains the growth of aggressive orthotopic breast tumors while suppressing pulmonary metastasis by eradicating CSC populations. The reported smart nanomedicine provides a new paradigm for redox imbalance-triggered cancer therapy.     

Smart Tumor Microenvironment‐Responsive Nanotheranostic Agent for Effective Cancer Therapy

The tumor microenvironment (TME), which includes acidic and hypoxic conditions, severely impedes the therapeutic efficacy of antitumor agents. Herein, MnO₂‐loaded, bovine serum albumin, and PEG co‐modified mesoporous CaSiO₃ nanoparticles (CaM‐PB NPs) are developed as a nanoplatform with sequential theranostic functions for the engineering of TME. The MnO₂ NPs generate O₂ in situ by reacting with endogenous H₂O₂, relieving the hypoxic state of the TME that further modulates the cancer cell cycle status to S phase, which improves the potency of co‐loaded S phase‐sensitive chemotherapeutic drugs. After the hypoxia relief, CaM‐PB can sustainably release drugs due to the enlarged pores of mesoporous CaSiO₃ in the acidic TME, preventing the drug pre‐leakage into the blood circulation and insufficient drug accumulation at tumor sites. Moreover, the Mn²⁺ released from the MnO₂ NPs at tumor sites can potentially serve as a diagnostic agent, enabling the identification of tumor regions by T₁‐weighted magnetic resonance imaging during therapy. In vivo pharmacodynamics results demonstrate that these synergetic effects caused by CaM‐PB NPs significantly contribute to the inhibition of tumor progression. Therefore, the CaM‐PB NPs with sequential theranostic functions are a promising system for effective cancer therapy.     

Biodegradable Fe(III)@WS2‐PVP Nanocapsules for Redox Reaction and TME‐Enhanced Nanocatalytic,Photothermal, and Chemotherapy

In this study, biocompatible Fe(III) species‐WS₂‐polyvinylpyrrolidone (Fe(III) @ WS₂‐PVP) nanocapsules with enhanced biodegradability and doxorubicin (DOX) loading capacity are one‐pot synthesized. In this nanocapsule, there exists a redox reaction between Fe(III) species and WS₂ to form Fe²⁺ and WO₄^2?. The formed Fe²⁺ could be oxidized to Fe³⁺, which reacts with Fe(III) @ WS₂‐PVP again to continuously produce Fe²⁺ and WO₄^2?. Such a repeated endogenous redox reaction leads to an enhanced biodegradation and DOX release of DOX @ Fe(III) @ WS₂‐PVP. More strikingly, the Fe²⁺ generation and DOX release are further accelerated by the overexpressed H₂O₂ and the mild acidic tumor microenvironment (TME), since H₂O₂ and H⁺ can accelerate the oxidation of Fe²⁺. The continuously generated Fe²⁺ catalyzes a fast Fenton reaction with the innate H₂O₂ in tumor cells and produces abundant highly toxic hydroxyl radicals for nanocatalytic tumor therapy. Together with the high photothermal transforming capability, the DOX @ Fe(III) @WS₂‐PVP nanocapsules successfully achieve the endogenous redox reaction and exogenous TME‐augmented tumor photothermal therapy, chemo and nanocatalytic therapy outcome. The concept of material design can be innovatively extended to the synthesis of biodegradable Fe(III) @ MoS₂‐PVP nanocomposite, thus paving a promising novel way for the rational design of intelligent theranostic agents for highly efficient treatment of cancer.     

A Novel Theranostic Nanoplatform Based on Pd@Pt‐PEG‐Ce6 for Enhanced Photodynamic Therapy by Modulating Tumor Hypoxia Microenvironment

Photodynamic therapy (PDT), which utilizes reactive oxygen species to kill cancer cells, has found wide applications in cancer treatment. However, the hypoxic nature of most solid tumors can severely restrict the efficiency of PDT. Meanwhile, the hydrophobicity and limited tumor selectivity of some photosensitizers also reduce their PDT efficacy. Herein, a photosensitizer‐Pd@Pt nanosystem (Pd@Pt‐PEG‐Ce6) is designed for highly efficient PDT by overcoming these limitations. In the nanofabrication, Pd@Pt nanoplates, exhibiting catalase‐like activity to decompose H₂O₂ to generate oxygen, are first modified with bifunctional PEG (SH‐PEG‐NH₂). Then the Pd@Pt‐PEG is further covalently conjugated with the photosensitizer chlorin e6 (Ce6) to get Pd@Pt‐PEG‐Ce6 nanocomposite. The Pd@Pt‐PEG‐Ce6 exhibits good biocompatibility, long blood circulation half‐life, efficient tumor accumulation, and outstanding imaging properties. Both in vitro and in vivo experimental results clearly indicate that Pd@Pt‐PEG‐Ce6 effectively delivers photosensitizers to cancer cells/tumor sites and triggers the decomposition of endogenous H₂O₂ to produce oxygen, resulting in a remarkably enhanced PDT efficacy. Moreover, the moderate photothermal effect of Pd@Pt nanoplates also strengthen the PDT of Pd@Pt‐PEG‐Ce6. Therefore, by integrating the merits of high tumor‐specific accumulation, hypoxia modulation function, and mild photothermal effect into a single nanoagent, Pd@Pt‐PEG‐Ce6 readily acts as an ideal nanotherapeutic platform for enhanced cancer PDT.     

Construction of VS2/VOx Heterostructure via Hydrolysis-Oxidation Coupling Reaction with Superior Sodium Storage Properties

Heterostructure engineering is one of the most promising modification strategies for reinforcing Na⁺ storage of transition metal sulfides. Herein, based on the spontaneous hydrolysis-oxidation coupling reaction of transition metal sulfides in aqueous media, a VO_x layer is induced and formed on the surface of VS₂, realizing tight combination of VS₂ and VO_x at the nanoscale and constructing homologous VS₂/VO_x heterostructure. Benefiting from the built-in electric field at the heterointerfaces, high chemical stability of VO_x, and high electrical conductivity of VS₂, the obtained VS₂/VO_x electrode exhibits superior cycling stability and rate properties. In particular, the VS₂/VO_x anode shows a high capacity of 878.2 mAh g⁻¹ after 200 cycles at 0.2 A g⁻¹. It also exhibits long cycling life (721.6 mAh g⁻¹ capacity retained after 1000 cycles at 2 A g⁻¹) and ultrahigh rate property (up to 654.8 mAh g⁻¹ at 10 A g⁻¹). Density functional theory calculations show that the formation of heterostructures reduces the activation energy for Na⁺ migration and increases the electrical conductivity of the material, which accelerates the ion/electron transfer and improves the reaction kinetics of the VS₂/VO_x electrode.     

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

Biohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe₃O₄ NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O₂ generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.     

Persistent Regulation of Tumor Microenvironment via Circulating Catalysis of MnFe2O4@Metal–Organic Frameworks for Enhanced Photodynamic Therapy

Reactive oxygen species (ROS)‐based cancer therapy, such as photodynamic therapy (PDT), is subject to the hypoxia and overexpressed glutathione (GSH) found in the tumor microenvironment (TME). Herein, a novel strategy is reported to continuously and simultaneously regulate tumor hypoxia and reducibility in order to achieve the desired therapeutic effect. To accomplish this, a biocompatible nanoplatform (MnFe₂O₄@metal–organic framework (MOF)) is developed by integrating a coating of porphyrin‐based MOF as the photosensitizer and manganese ferrite nanoparticle (MnFe₂O₄) as the nanoenzyme. The synthetic MnFe₂O₄@MOF nanoplatform exhibits both catalase‐like and glutathione peroxidase‐like activities. Once internalized in the tumor, the nanoplatform can continuously catalyze H₂O₂ to produce O₂ to overcome the tumor hypoxia by cyclic Fenton reaction. Meanwhile, combined with the Fenton reaction, MnFe₂O₄@MOF is able to persistently consume GSH in the presence of H₂O₂, which decreases the depletion of ROS upon laser irradiation during PDT and achieves better therapeutic efficacy in vitro and in vivo. Moreover, the nanoplatform integrates a treatment modality with magnetic resonance imaging, along with persistent regulation of TME, to promote more precise and effective treatment for future clinical application.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

Unveiling the Multiple Tumor-Targeted Impairments of Covalent-Organic Framework-Switched Photothermal Shielding Nanoparticles

Covalent organic framework (COF) receives great attention in biomedical applications due to its variable compositions and ordered structures. However, its targeted design to achieve desirable physiological functions especially for cancer treatments remains elusive. Herein, PEGylated COF with tumor-specific TKD peptide modification is uniformly coated on photothermal mesoporous carbon nanospheres via polyethyleneimine-mediated interface polymerization to construct a multifunctional core-shell nanoparticle (OPCPT). Physicochemical studies demonstrate near infrared (NIR)-blocking ability of the crystalline COF shells under physiological conditions, whereas COF is degraded under the acidic tumor microenvironments (TME). Subsequently, the nanoparticle charge is reversed and the COF monomers can produce ¹O₂/O₂. As a result, OPCPT, activated in the TME due to the shell dissociation, penetrates deeply into tumors through positive charge-mediated/lysosome rupture-mediated transcytosis and recovers its NIR-heating potential for tumor-specific photothermal therapy. Moreover, the TME-triggered ¹O₂ significantly depresses the lysosome autophagy via membrane destruction, and selectively damages the mitochondria to promote the cytochrome C release-activated apoptosis and ATP deficiency-inhibited tumor metastasis. Particularly, this unique O₂ generation mechanism relieves the tumor hypoxia upon the reactive oxygen species therapy and downregulates hypoxia-inducible factor and its downstream proteins, which all contribute to augmented tumor therapy. The findings represent a remarkable unveiling of the potential of COF-based nanomaterials for extended biomedical applications.     

A Metal-Free Mesoporous Carbon Dots/Silica Hybrid Type I Photosensitizer with Enzyme-Activity for Synergistic Treatment of Hypoxic Tumor

As a less O₂-dependent photodynamic therapy (PDT), type I PDT is an effective approach to overcome the hypoxia-induced low efficiency against solid tumors. However, the commonly used metal-involved agents suffer from the long-term biosafety concern. Herein, a metal-free type I photosensitizer, N-doped carbon dots/mesoporous silica nanoparticles (NCDs/MSN, ≈40 nm) nanohybrid with peroxidase (POD)-like activity for synergistic PDT and enzyme-activity treatment, is developed on gram scale via a facile one-pot strategy through mixing carbon source and silica precursor with the assistance of template. Benefiting from the narrow bandgap (1.92 eV) and good charge separation capacity of NCDs/MSN, upon 640 nm light irradiation, the excited electrons in the conduction band can effectively generate O₂^•− by reduction of dissolved O₂ via a one-electron transfer process even under hypoxic conditions, inducing apoptosis of tumor cells. Moreover, the photoinduced O₂^•− can partially transform into more toxic ^•OH through a two-electron reduction. Moreover, the POD-like activity of NCDs/MSN can catalyze the endogenous H₂O₂ to ^•OH in the tumor microenvironment, further synergistically ablating 4T1 tumor cells. Therefore, a mass production way to synthesize a novel metal-free type I photosensitizer with enzyme-mimic activity for synergistic treatment of hypoxic tumors is provided, which exhibits promising clinical translation prospects.     

Electrochemically Induced Crystalline-to-Amorphous Transition of Dinuclear Polyoxovanadate for High-Rate Lithium-Ion Batteries

Polyoxometalates are intriguing high-capacity anode materials for alkali-metal-ion storage due to their multi-electron redox capabilities and flexible structure. However, their poor electrical conductivity and high working voltage severely restrict their practical application. Herein, the dinuclear polyoxovanadate Sr₂V₂O₇·H₂O with unusually high electrical conductivity is reported as a promising anode material for lithium-ion batteries. During the initial lithiation process, the Sr₂V₂O₇·H₂O anode experiences an electrochemically induced crystalline-to-amorphous transition. The resulting amorphous structure provides high redox activity and fast reaction kinetics via reversible V^4.9+/V^2.8+ redox couple through the intercalation mechanism. Furthermore, when coupled with the LiFePO₄ cathode, the strong V O bonds of the amorphous anode provide excellent structural stability, with the full-cell capable of performing >12 000 cycles with a capacity retention of 72%. Another advantage of Sr_2xV₂O_7-δ·yH₂O (0.5 ≤ x ≤ 1.0) is its composition adjustability, which enables delicately regulating the Sr vacancy content without destroying the structure. The defect Sr_2xV₂O_7-δ·yH₂O (x = 0.5) electrodes show significantly improved specific capacity and rate capability without sacrificing other key properties, delivering a high specific capacity of 479 mAh g^-1 at 0.1 mA cm^-2 and 41.9% of its capacity in 2 min. Overall, the preliminary study points the way forward for the facile preparation of high-quality polyoxometalates for advanced energy storage applications and beyond.     

Bioresponsive Self-Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune-Related Adverse Events in Tumor Immunotherapy

Despite the immense potential of immune checkpoint blockade (ICB) therapy in tumor treatment, its widespread clinical application is currently limited by unsatisfactory curative effect and off-target adverse effect. Herein, an injectable sericin (SS)/silk fibroin (SF) recombinant hydrogel, termed SF-SS-SMC hydrogel, is developed to enable local delivery of anti-CD47 antibody (α CD47). The hydrogel displays self-reinforcement in high H₂O₂ concentration of tumor microenvironment (TME), as the SS/Fe²⁺ supramolecular nanocomplex (SS-SMC) inside the hydrogel converts H₂O₂ to reactive oxygen species (ROS), further triggering additional crosslinking among the SF polymers. Therefore, the SF-SS-SMC hydrogel has an in vivo retention time longer than 21 days and acts as a reservoir for the long-term sustained release of α CD47. More importantly, the SF-SS-SMC hydrogel itself efficiently regulates the remodeling of a protumor immunosuppressive TME to an antitumoral TME through switching of tumor-associated macrophages from an anti-inflammatory M2 phenotype to a proinflammatory M1 phenotype without additional drugs. Based on the combined effect of sustained α CD47 release and TME reprogramming, the SF-SS-SMC hydrogel has satisfactory immunotherapeutic effects in the treatment of local, abscopal, remitting, and metastatic tumors. Further advantages, including low cost of production, simple fabrication, and ease of use, make it promising for commercial mass production.     

Palladium Nanocrystals-Engineered Metal–Organic Frameworks for Enhanced Tumor Inhibition by Synergistic Hydrogen/Photodynamic Therapy

Hydrogen therapy, as a star therapeutic modality, has recently acquired much attention in the field of anticancer medicine. Evidence suggests that hydrogen can selectively reduce intratumoral overexpressed hydroxyl radicals (•OH) to break the redox homoeostasis and thereby result in redox stress and cell damage. As a reactive oxygen species-related noninvasive modality, photodynamic therapy (PDT) has been approved for varied tumor treatments clinically. For implementing tumor therapy with enhanced anticancer efficacy and attenuated side effects, here a biocompatible palladium nanocrystals-integrated nanoscale porphyrinic metal–organic framework (NPMOF) is designed to develop a novel combined therapy modality, that is, synergistic hydrogen/photodynamic therapy. The NPMOF is employed simultaneously as the photosensitizer for PDT and as the nanocarrier to support palladium nanocrystals, which is further used as the hydrogen vehicle. The final hydrogen-containing nanosystems exhibit a persistent reductive hydrogen release behavior and considerable light-activated singlet oxygen (¹O₂) generation without mutual interference, contributing to the adequate disturbance of tumor microenvironment redox steady-state for synergistically inducing tumor cell death. Ultimately, by coupling of tumor-selective hydrogen therapy and PDT, the designed nanosystems realize the augmented therapeutic outcome with minimal side effects, providing a safe and efficient tumor treatment for future clinical translation.     

Intracellular Mutual Promotion of Redox Homeostasis Regulation and Iron Metabolism Disruption for Enduring Chemodynamic Therapy

Intracellular redox homeostasis and the iron metabolism system in tumor cells are closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite extensive attempts, maintaining high levels of intracellular catalysts (free iron) and reactants (H₂O₂) while decreasing the content of reactive oxygen species (ROS) scavengers (especially glutathione (GSH)) for enduring CDT still remains great challenges. Herein, S S bond-rich dendritic mesoporous organic silica nanoparticles (DMON) are utilized as GSH-depleting agents. After co-loading Fe⁰ and a catalase inhibitor (3-amino-1,2,4-triazole (AT)), a novel biodegradable nanocarrier is constructed as DMON@Fe⁰/AT. In the mildly acidic tumor microenvironment, on-demand ferrous ions and AT are intelligently released. AT suppresses the activity of catalase for H₂O₂ hoarding, and the exposed DMON weakens ROS scavenging systems by persistently depleting intracellular GSH. The highly efficient •OH production by DMON@Fe⁰/AT can effectively attack mitochondria and downregulate the expression of ferroportin 1, which can disrupt the cellular iron metabolism system, leading to the desired retention of iron in the cytoplasm. More importantly, DMON@Fe⁰/AT exhibits a much more efficient CDT killing effect on 4T1 tumor cells than plain Fe⁰ nanoparticles, benefiting from their synergistic redox regulation and iron metabolism disruption. Overall, the as-prepared intelligent, degradable DMON@Fe⁰/AT provides an innovative strategy for enduring CDT.     

High‐Security Nanocluster for Switching Photodynamic Combining Photothermal and Acid‐Induced Drug Compliance Therapy Guided by Multimodal Active‐Targeting Imaging

High‐security nanoplatform with enhanced therapy compliance is extremely promising for tumor. Herein, using a simple and high‐efficient self‐assembly method, a novel active‐targeting nanocluster probe, namely, Ag₂S/chlorin e6 (Ce6)/DOX@DSPE‐mPEG₂₀₀₀‐folate (ACD‐FA) is synthesized. Experiments indicate that ACD‐FA is capable of specifically labeling tumor and guiding targeting ablation of the tumor via precise positioning from fluorescence and photoacoustic imaging. Importantly, the probe is endowed with a photodynamic “on‐off” effect, that is, Ag₂S could effectively quench the fluorescence of chlorin e6 (89.5%) and inhibit release of ¹O₂ (92.7%), which is conducive to avoid unwanted phototoxicity during transhipment in the body, and only after nanocluster endocytosed by tumor cells could release Ce6 to produce ¹O₂. Moreover, ACD‐FA also achieves excellent acid‐responsive drug release, and exhibits eminent chemo‐photothermal and photodynamic effects upon laser irradiation. Compared with single or two treatment combining modalities, ACD‐FA could provide the best cancer therapeutic effect with a relatively low dose, because it made the most of combined effect from chemo‐photothermal and controlled photodynamic therapy, and significantly improves the drug compliance. Besides, the active‐targeting nanocluster notably reduces nonspecific toxicity of both doxorubicin and chlorin e6. Together, this study demonstrates the potency of a newly designed nanocluster for nonradioactive concomitant therapy with precise tumor‐targeting capability.