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Given that tumor microenvironment (TME) exerts adverse impact on the therapeutic response and clinical outcome, robust TME modulators may significantly improve the curative effect and increase survival benefits of cancer patients. Here, Au nanodots-anchored CoFe 2 O 4 nanoflowers with PEGylation (CFAP) are developed to respond to TME cues, aiming to exacerbate redox dyshomeostasis for efficacious antineoplastic therapy under ultrasound (US) irradiation. After uptake by tumor cells, CFAP with glucose oxidase (GOx)-like activity can facilitate glucose depletion and promote the production of H 2 O 2 . Multivalent elements of Co(II)/Co(III) and Fe(II)/Fe(III) in CFAP display strong Fenton-like activity for·OH production from H 2 O 2 . On the other hand, energy band structure CFAP is superior for US-actuated 1 O 2 generation, relying on the enhanced separation and retarded recombination of e - /h + pairs. In addition, catalase-mimic CFAP can react with cytosolic H 2 O 2 to generate molecular oxygen, which may increase the product yields from O 2 -consuming reactions, such as glucose oxidation and sonosensitization processes. Besides the massive production of reactive oxygen species, CFAP is also capable of exhausting glutathione to devastate intracellular redox balance. Severe immunogenic cell death and effective inhibition of solid tumor by CFAP demonstrates the clinical potency of such heterogeneous structure and may inspire more relevant designs for disease therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to develop innovative drug delivery system based on nano-strategies., Result: In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect., Conclusion: The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy., (© 2021. The Author(s).)

The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor-specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual-responsive nano-prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual-responsive system facilitates the nano-prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo-photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo-photodynamic therapy and control-release PTX synergistically induce gasdermin E (GSDME)-related pyroptosis. It is speculated that inspired chemo-photodynamic therapy using the presented nano-prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Silk fibroin (SF), derived from Bombyx mori, is a category of fibrous protein with outstanding potential for applications in the biomedical and biotechnological fields. In spite of its many advantageous properties, the exploration of SF as a versatile nanodrug precursor for tumor therapy has still been restricted in recent years. Herein, a multifunctional SF-derived nanoplatform was facilely developed via encapsulating the photosensitizer chlorin e6 (Ce6) into MnO2-capped SF nanoparticles (NPs). SF@MnO2 nanocarriers were synthesized through a surface crystallization technique, using SF as a reductant and sacrificial template. Afterwards, Ce6 was covalently incorporated into the loose structure of the SF@MnO2 nanocarrier on the basis of adsorption to abundant peptide-binding sites. To modulate the tumor microenvironment (TME), SF@MnO2/Ce6 (SMC) NPs were capable of catalyzing the decomposition of H2O2 into O2, which can be converted into cytotoxic reactive oxygen species (ROS) during photodynamic therapy (PDT). Moreover, the MnO2 component was able to oxidize intracellular glutathione (GSH) into non-reducing glutathione disulfide (GSSG), and the consumption of GSH could significantly protect the local ROS from being reduced, which further augmented the therapeutic outcome of PDT. Via another angle, SMC NPs can produce strong hyperthermia under near-infrared (NIR) light activation, which was highly desirable for efficient photothermal therapy (PTT). Both in vitro and in vivo studies demonstrated the intense tumor inhibitory effects as a result of augmented PTT/PDT mediated by SMC NPs. We believe that this study may provide useful insights for employing SF-based nanocomposites for more medical applications in the near future.

Background: Reactive oxygen species (ROS), as a category of highly reactive molecules, are attractive for eliminating tumor cells in situ . However, the intrinsic tumor microenvironment (TME) always compromises treatment efficacy. In another aspect, silk fibroin (SF), as a category of natural biomacromolecules, is highly promising for synthesis of metallic nanocrystals via biomineralization. Methods: As a proof-of-concept study, AuPt bimetallic nanozyme derived from bioinspired crystallization of chloroauric acid and chloroplatinic acid was facilely developed in the presence of silk fibroin (SF). Antitumor effects caused by the as-synthesized AuPt@SF (APS) nanozyme were demonstrated in 4T1 tumor cells in vitro and xenograft tumor models in vivo . Results: APS nanozyme can decompose glucose to constantly supply H 2 O 2 and deplete intracellular glutathione (GSH). APS nanozyme can simultaneously convert adsorbed O 2 and endogenic H 2 O 2 into superoxide radicals ( • O 2 - ) and hydroxyl radical ( • OH), respectively, upon highly efficient catalytic reaction. Subsequently, these cytotoxic ROS cause irreversible damage to the cell membrane, nucleic acid and mitochondria of tumors. Upon fluorescence/photoacoustic (FL/PA)-imaging guidance, remarkable tumor damage based on the current nanoplatform was confirmed in vivo . Conclusion: The objective of our investigation is to supply more useful insights on the development of SF-based nanocatalysts, which are specifically responsive to TME for extremely efficient tumor theranostics., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Chemodynamic therapy (CDT), an emerging therapeutic strategy, has been recently exploited for in situ treatment through Fenton or Fenton-like reactions to generate cytotoxic reactive oxygen species (ROS). However, current systems rely significantly on the high local oxygen levels and strongly acidic conditions (pH = 3.0-5.0). Simultaneously, the produced ROS can be rapidly consumed by intracellular glutathione (GSH) in the electron transport chain. Herein, an original and biomimetic CoO@AuPt nanocatalyst was prepared based on the assembly of Au and Pt nanoparticles (NPs) on the surface of hollow CoO nanocapsules. The as-synthesized nanozyme exhibits extremely high stability under physiological conditions, whereas it undergoes spontaneous disintegration in the unique tumor microenvironment (TME). Subsequently, the decomposition products can catalyze a cascade of biochemical reactions to produce abundant ROS without any external stimuli. Thus, the present nanoplatform can increase intracellular ROS levels through continuous supply of H 2 O 2 , relief of local hypoxia and depletion of GSH, which result in remarkable and specific tumor damage both in vitro and in vivo. The findings of this study highlight the promising potential of CoO@AuPt nanocatalyst as a TME-responsive CDT nanomagnet for highly efficient tumor therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Anticancer nanomedicine-based multimodal imaging and synergistic therapy hold great promise in cancer diagnosis and therapy owing to their abilities to improve therapeutic efficiency and reduce unnecessary side effects, producing promising clinical prospects. Herein, we integrated chemotherapeutic drug camptothecin (CPT) and near-infrared-absorbing new indocyanine green (IR820) into a single system by charge interaction and obtained a tumor-microenvironment-activatable PCPT SS /IR820 nanoreactor to perform thermal/fluorescence/photoacoustic-imaging-guided chemotherapy and photothermal therapy simultaneously. Specifically, the generated PCPT SS /IR820 showed an excellent therapeutic agent loading content and size stability, and the trials in vitro and in vivo suggested that the smart PCPT SS /IR820 could deeply permeate into tumor tissues due to its suitable micellar size. Upon near-infrared laser irradiation, the nanoreactor further produced a terrific synergism of chemo-photo treatment for cancer therapy. Therefore, the PCPT SS /IR820 polyprodrug-based nanoreactor holds outstanding promise for multimodal imaging and combined dual therapy.

Low delivery efficiency and limited tumor penetration of nanoparticle-based drug delivery systems (DDSs), the two most concerned issues in tumor therapy, have been considered as the "Achilles' heel" for tumor treatment. In this study, we have designed a highly sensitive dual-redox-responsive prodrug-based starlike polymer β-CD- b -P(CPT GSH - co -CPT ROS - co -OEGMA) (CP GR ) for synergistic chemotherapy. The high glutathione (GSH) concentration and high reactive oxygen species (ROS) levels are in a dynamic equilibrium in the tumor microenvironment (TME) and could trigger the disintegration of CP GR micelles, which can promote the release of anticancer drug camptothecin (CPT) completely and intelligently. In order to verify the synergistic antitumor mechanism, two corresponding single-responsive β-CD- b -P(CPT GSH - co -OEGMA) (CP G ) and β-CD- b -P(CPT ROS - co -OEGMA) (CP R ) were altogether prepared as contrast. Both in vitro and in vivo studies confirmed the enhanced anticancer activity of CP GR micelles in comparison of single responsive micelles. This work contributes to the orchestrated design of dual-redox-responsive DDSs for synergetic antitumor chemotherapy, which provides a good approach for the development of dual-redox-responsive nanomedicine.

The physicochemical properties of nanomedicine can be altered with a tumor microenvironment, which influence the precise delivery of drug molecules to the lesion. Thus, the therapeutic efficiency is restrained. Here, a covalent self-assembled nanomicelle (CSNM) based starburst polyprodrug was constructed with the unimolecular micelle-templated self-assembly method and was expected to overcome biological barriers. It aimed to enhance the tumor penetration and chemotherapy efficiency of drugs. In CSNM, a hydrophilic copolymer was glued around a camptothecin (CPT) linked starburst polymeric prodrug [β-CD-P (CPT- co-NH 2 )] for protecting the positive charge of the prodrug with a reduction-triggered reversibility in conjugation and activity. Then, the complex was tracelessly delivered into a negatively charged cell membrane, leading to enhanced cellular uptake. Finally, the disulfide bond in the CPT prodrug can be broken under the reductive microenvironment within tumor cells and liberated the CPT molecules. Both in vitro and in vivo results demonstrated the benefits of our CSNM system, including high drug loading, controllable drug release, excellent uptake by tumor cells and remarkable antitumor efficiency. In essence, our findings suggested CSNM as an innovative strategy for drug delivery in chemotherapy, producing a competitive versatility in the development of biomedicine.

Cancer immunotherapy has the potential to revolutionize the treatment of malignant tumors, but its effectiveness is limited by the low immune response rate and immune‐related adverse events. Pyroptosis, as an inflammatory programmed cell death type, triggers strong acute inflammatory response and antitumor immunity, converting "cold" tumors to "hot". Particularly, biomaterials loading pyroptosis inducers targeting the tumor microenvironment to engineer pyroptosis, have achieved great progress in recent years. Herein, the design strategy, mechanism pathway, and role of biomaterials to induce pyroptosis in cancer immunotherapy are comprehensively reviewed. The present review focuses on the application of biomaterials‐induced pyroptosis in cancer immunotherapy, including nanogel, polymer prodrug, nanovesicle, and mesoporous material. Additionally, the synthesis of a series of stimuli‐responsive nanoplatforms, including glutathione‐responsive, pH‐responsive, reactive oxygen species‐responsive, and enzyme‐mimicking catalytic performance, is described. Meanwhile, it augments multiple immune response processes of cell uptake, antigen presentation, T‐cell activation, and expansion. Finally, the perspectives of pyroptosis‐mediated inflammation to break through the tumor vascular basement membrane barrier achieving efficient volcanic penetration of biomaterials are discussed. Artificial intelligence, multi‐omics analysis, and anthropogenic animal models of organoids are presented, aiming to provide guidance and assistance for constructing effective and controllable pyroptosis‐engineered biomaterials and improving tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (α PD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy. A GSH-activable prodrug nanomicelle co-delivering PI3K/mTOR inhibitor PF-04691502 and broad spectrum CDK inhibitor flavopiridol for potentiating cancer immunotherapy is developed. [Display omitted] [ABSTRACT FROM AUTHOR]

Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe2+/Fe3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

Ion homeostasis distortion through exogenous overload or underload of intracellular ion species has become an arresting therapeutic approach against malignant tumor. Nevertheless, treatment outcomes of such ion interference are always compromised by the intrinsic ion homeostasis maintenance systems in cancer cells. Herein, an ion homeostasis perturbator (CTC) is facilely designed by co-encapsulation of carvacrol (CAR) and meso-tetra-(4-carboxyphenyl)porphine (TCPP) into pH-sensitive nano-CaCO 3 , aiming to disrupt the self-defense mechanism during the process of ion imbalance. Upon the endocytosis of CTC into tumor cells, lysosomal acidity can render the decomposition of CaCO 3 , resulting in the instant Ca2+ overload and CO 2 generation in cytoplasm. Simultaneously, CaCO 3 disintegration triggers the release of CAR and TCPP, which are devoted to TRPM7 inhibition and sonosensitization, respectively. The malfunction of TRPM7 can impede the influx of Mg2+ and allow unrestricted influx of Ca2+ based on the antagonism relationship between Mg2+ and Ca2+, leading to an aggravated Ca2+/Mg2+ dyshomeostasis through ion channel deactivation. In another aspect, US-triggered cavitation can be significantly enhanced by the presence of inert CO 2 microbubbles, further amplifying the generation of reactive oxygen species. Such oxidative damage-augmented Ca2+/Mg2+ interference therapy effectively impairs the mitochondrial function of tumor, which may provide useful insights in cancer therapy. [ABSTRACT FROM AUTHOR]

Intracellular redox dyshomeostasis promoted by tumor microenvironment (TME) modulation has become an appealing therapeutic target for cancer management. Herein, a dual plasmonic Au/SF@Cu 2-x S nanoreactor (abbreviation as ASC) is elaborately developed by covalent immobilization of sulfur defective Cu 2-x S nanodots onto the surface of silk fibroin (SF)-capped Au nanoparticles. Tumor hypoxia can be effectively alleviated by ASC-mediated local oxygenation, owing to the newfound catalase-mimic activity of Cu 2-x S. The semiconductor of Cu 2-x S with narrow bandgap energy of 2.54 eV enables a more rapid dissociation of electron-hole (e−/h+) pair for a promoted US-triggered singlet oxygen (1O 2) generation, in the presence of Au as electron scavenger. Moreover, Cu 2-x S is devote to Fenton-like reaction to catalyze H 2 O 2 into ·OH under mild acidity and simultaneously deplete glutathione to aggravate intracellular oxidative stress. In another aspect, Au nanoparticles with glucose oxidase-mimic activity consumes intrinsic glucose, which contributes to a higher degree of oxidative damage and energy exhaustion of cancer cells. Importantly, such tumor starvation and 1O 2 yield can be enhanced by Cu 2-x S-catalyzed O 2 self-replenishment in H 2 O 2 -rich TME. ASC-initiated M1 macrophage activation and therapy-triggered immunogenetic cell death (ICD) favors the systematic tumor elimination by eliciting antitumor immunity. This study undoubtedly enriches the rational design of SF-based nanocatalysts for medical utilizations. [ABSTRACT FROM AUTHOR]

Endogenous H 2 O 2 sacrifices for diversified therapeutic reactions against tumor. However, the treatment outcome is not always satisfactory owing to the unsustainable H 2 O 2 supply from tumor microenvironment (TME). Herein, a platinum (Pt) nanourchin-based multi-enzymatic platform (referred to PGMA) is established by surface conjugation of glucose oxidase (GOx) capped with manganese carbonyl (MnCO) and loading 3-amino-1,2,4-triazole (3-AT). The mild acidic and H 2 O 2 -rich TME can render the degradation of MnCO, followed by triggering the release of CO gas, 3-AT and Mn2+/3+. The resultant GOx exposure initiates intratumoral glucose depletion, which is promoted by the O 2 replenishment through Pt-catalyzed decomposition of H 2 O 2. Meanwhile, intracellular reactive oxygen species (ROS) level is elevated through Mn2+/3+ couple-mediated Fenton-like reaction. Hence, CO release-initiated gas therapy, glucose exhaustion-induced tumor starvation and ROS-triggered chemodynamic therapy are committed to realizing a combinatorial disruption effect on mitochondrial function. Importantly, the released 3-AT can inhibit the activity of endogenous catalase, which effectively elevates the intracellular H 2 O 2 level to compensate its consumption and provides incremental reactant for cascade utilizations. Taken together, this study aims to emphasize the importance of intracellular H 2 O 2 balance during H 2 O 2 -depleted therapeutic process, and affords a prime paradigm of applying this strategy for tumor treatment via mitochondrial dysfunction. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A bioresponsive DPH prodrug nanogels were synthesized by conjugating purpurin 18 with 10-hydroxycamplothecin. • The high glutathione will be consumed, and ROS can be generated after laser irradiation. • Excess ROS damages the mitochondria, thus exhibit low Δψm, exerting long-term oxidative stress. • The DPH nanogel showed an enhanced chemo-photodynamic therapy with real-time MR/NIRF dual-modal imaging. Currently single photosensitizers or chemotherapeutics implemented in clinic present huge challenges in terms of non-selective toxicity, physiological instability and unfavorable therapeutic efficacy. Herein, we designed a versatile polycondensate-based strategy for the preparation of redox-responsive prodrug nanogels (NGs) for enhanced synergistic cancer therapy. Concretely, based on a reductive cross-linking of purpurin 18 (P18) and 10-hydroxycamplothecin (HCPT), a well-designed prodrug nanogel (denoted as DPH NGs) with suitable size (~67 nm) was fabricated, which exhibited high drug loading, controlled drug release and deepened tumor penetration. The high concentration of glutathione (GSH) in the tumor microenvironment (TME) is capable of being consumed by dense disulfide bonds in DPH NGs, promoting the generation of reactive oxygen species (ROS) after irradiation at 660 nm, thus reshape the TME to reinforce photodynamic therapy against malignancies. In addition, P18 can be served as a powerful NIR fluorescence (NIRF)/ magnetic resonance (MR) imaging ability. Pleasantly, DPH NGs showed amplified oxidative stress in tumor cells to achieve an enhanced chemo-photodynamic therapy with the real-time MR/NIRF dual-modal imaging. Our findings in this study may blow up a storm for devising a simple and versatile strategies for multi-drug delivery and combined cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • A H 2 O 2 self-supplying nanoreactor-based sericin is prepared for enhanced chemodynamic therapy. • The generation of H 2 O 2 enhances the efficiency of Fenton reaction and improves the efficacy of chemodynamic therapy (CDT). • The pH-triggered behaviors of doxorubicin and H 2 O 2 are confirmed. • The decoration of sericin endows nanoreactor excellent hydrophilicity and biocompatibility. Facing the multiple and arduous characteristics of tumors, chemodynamic therapy (CDT) is an emerging therapeutic approach. It uses toxic hydroxyl radical (∙OH) produced by Fenton reaction to induce cell apoptosis, which is not restricted by other factors such as the limitations of tissue depth and hypoxic tumor microenvironment. However, the problem of insufficient endogenous hydrogen peroxide (H 2 O 2) seriously restricts its development and widespread use. In this study we developed a new type of nano-Fenton catalyst SS-CuO 2 @Dox (SCD), which was prepared by the peroxidation reaction of Cu2+. Under the decoration of sericin, it had excellent hydrophilicity and biocompatibility, and could target the tumor regions via the enhanced permeability and retention (EPR) effect. It could be decomposed under the acidic conditions of the tumor microenvironment (TME) and endogenously released H 2 O 2 and Cu2+, which enhanced the efficiency of the Fenton reaction. At the same time, the successful delivery of doxorubicin (Dox), a chemotherapeutic drug, realized the combination of chemotherapy and CDT, improving the therapeutic effect of tumor. The strategy of generating H 2 O 2 in situ could solve the problem of insufficient H 2 O 2 in tumor without causing damage to other tissues and organs. This treatment provided a new idea for enhanced CDT and synergistic therapy, showing a promising prospect of application. [ABSTRACT FROM AUTHOR]