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[Display omitted] Glioma is a prevalent brain malignancy associated with poor prognosis. Although chemotherapy serves as the primary treatment for brain tumors, its effectiveness is hindered by the limited ability of drugs to traverse the blood–brain barrier (BBB) and the development of drug resistance linked to tumor hypoxia. Herein, we report the creation of hybrid camouflaged multifunctional nanovesicles comprising membranes of tumor C6 cells (mT) and bacterial outer membrane vesicles (OMVs) and co-loaded with manganese dioxide nanoparticles (MnO 2 NPs) and doxorubicin (DOX) to synergistically enhance the chemotherapy/chemodynamic therapy (CDT) of glioma. Owing to OMV-mediated BBB penetration and mT-inherited tumor-homing properties, MnO 2 -DOX@mT/OMVs can penetrate the BBB and enhance the tumor cell-specific uptake of DOX via "proton sponge effect"-mediated lysosomal escape. This enhances the apoptotic effect induced by DOX and minimizing DOX-associated cardiotoxicity by facilitating the accumulation of DOX at the tumor site. Furthermore, the MnO 2 NPs in MnO 2 -DOX@mT/OMVs can generate potent CDT by accelerating the Fenton-like reaction with DOX-generated H 2 O 2 and achieving glutathione (GSH)-depletion-induced glutathione peroxidase 4 (GPX4) inactivation. These results showed that MnO 2 -DOX@mT/OMVs, designed for brain tumor targeting, significantly inhibited tumor growth and exhibited favorable biological safety. This innovative approach offers the augmentation of anticancer treatment efficacy via a potential combination of chemotherapy and CDT. [ABSTRACT FROM AUTHOR]

[Display omitted] Chemodynamic therapy (CDT) via Fenton-like reaction is greatly attractive owing to its capability to generate highly cytotoxic •OH radicals from tumoral hydrogen peroxide (H 2 O 2). However, the antitumor efficacy of CDT is often challenged by the relatively low radical generation efficiency and the high levels of antioxidative glutathione (GSH) in tumor microenvironment. Herein, an innovative photothermal Fenton-like catalyst, Fe-chelated polydopamine (PDA@Fe) nanoparticle, with excellent GSH-depleting capability is constructed via one-step molecular assembly strategy for dual-modal imaging-guided synergetic photothermal-enhanced chemodynamic therapy. Fe(III) ions in PDA@Fe nanoparticles can consume the GSH overexpressed in tumor microenvironment to avoid the potential •OH consumption, while the as-produced Fe(II) ions subsequently convert tumoral H 2 O 2 into cytotoxic •OH radicals through the Fenton reaction. Notably, PDA@Fe nanoparticles demonstrate excellent near-infrared light absorption that results in superior photothermal conversion ability, which further boosts above-mentioned cascade catalysis to yield more •OH radicals for enhanced CDT. Taken together with T 1 -weighted magnetic resonance imaging (MRI) contrast enhancement (r 1 = 8.13 mM−1 s−1) and strong photoacoustic (PA) imaging signal of PDA@Fe nanoparticles, this design finally realizes the synergistic photothermal-chemodynamic therapy. Overall, this work offers a new promising paradigm to effectively accommodate both imaging and therapy functions in one well-defined framework for personalized precision disease treatment. [ABSTRACT FROM AUTHOR]

Bacterial infection of wound surfaces has posed a significant threat to human health and represents a formidable challenge in the clinical treatment. In this study, a novel antimicrobial hydrogel utilizing POM is synthesized as the primary component, with gelatin and sodium alginate as the structural framework. The resultant hydrogel demonstrates exceptional mechanical properties and viscoelasticity attributed to the hydrogen‐bonded cross‐linking between POM and gelatin, as well as the ionic cross‐linking between sodium alginate and Ca2+. In addition, the integration of CuS nanoparticles conferred photothermal properties to the hydrogel system. To address the concerns regarding the potential thermal damage to the surrounding normal cells, this study employs a LT‐PTT combined with CDT approach to achieve the enhanced antimicrobial efficacy while minimizing the inadvertent harm to the healthy cells. The findings suggested that POM‐based hydrogels, serving as an inorganic–organic hybrid material, will represent a promising antimicrobial solution and offer valuable insights for the development of the non‐antibiotic materials. [ABSTRACT FROM AUTHOR]

[Display omitted] Single-atom nanozymes (SANZs) have emerged as new media for enhancing chemodynamic therapy (CDT) to achieve desirable enzyme-like effects and excellent nanoscale specificity. However, non-optimal adsorption of Fenton-like reaction intermediates prevents SANZs from exerting kinetic activity and hinders the CDT effect. Herein, we demonstrate that heteroatom-doped Co single-atom nanozymes (SACNZs) with intrinsic charge transfer exhibit peroxidase-like properties and significantly improve the ability of CDT to treat Staphylococcus aureus -infected wounds. Density functional theory calculations showed that the S-induced charge transfer effect regulated the electronic distribution of the central metal more efficiently than P, thereby lowering the energy levels for the generation of OH and increasing the catalytic effect. Polyvinylpyrrolidone-modified SACNZs showed effects consistent with this theory in both in vitro antibacterial and in vivo ward management assays. This study systematically investigated the relationship between heteroatom-doping and the catalytic activity of metal centres, opening a new perspective for the application of CDT. [ABSTRACT FROM AUTHOR]

The significance of the tumor microenvironment (TME) in tumor initiation and progression is increasingly acknowledged. Conventional therapeutic approaches face limitations within the complex TME, including the restrictions imposed by hypoxia on photodynamic therapy (PDT) and the deficiency of endogenous H₂O₂ affecting chemodynamic therapy (CDT). In response to the TME's characteristics of high metabolism, hypoxia, and weak acidity, a multifunctional nanosystem MNPs/GOD@CS/IR820, which synergistically integrates CDT and PDT, has been developed. This system can actively accumulate at tumor sites under an external magnetic field and release active components in response to the weakly acidic TME. It mitigates the limitations imposed by hypoxia and endogenous H₂O₂ deficiency on PDT and CDT, respectively, thereby enabling synergistic treatment. Additionally, the system's multimodal imaging capabilities facilitate precise tumor localization and real-time, non-invasive in vivo assessment via fluorescence imaging and MRI. In vitro and in vivo evaluations demonstrate significant antitumor efficacy, effectively inhibiting tumor growth and improving survival rates. By comprehensively addressing the challenges posed by the complex TME and enhancing real-time monitoring capabilities, our nanosystem paves the way for personalized and precise cancer treatment. This study introduces an innovative MNPs/GOD@CS/IR820 nanosystem that represents a significant advancement in cancer nanomedicine by addressing critical limitations of conventional photodynamic therapy (PDT), particularly in hypoxic tumor microenvironments. By synergistically integrating chemodynamic therapy (CDT) with PDT and incorporating MRI and fluorescence dual-modal imaging capabilities, this multifunctional platform offers enhanced therapeutic efficacy and real-time monitoring. The system's ability to generate oxygen in situ overcomes hypoxia-induced limitations, while its multimodal mechanism of action induces tumor cell apoptosis through multiple pathways. In vitro and in vivo studies demonstrate remarkable antitumor efficacy across diverse cancer types, significantly inhibiting tumor growth and improving survival rates. This comprehensive approach to cancer diagnosis and treatment not only advances precision medicine for targeted, multimodal cancer management but also provides a promising foundation for future clinical applications, potentially transforming cancer treatment strategies and improving patient outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Cancer cells engage in active aerobic glycolysis to meet their bioenergetic synthesis needs, which is known as the Warburg effect. Such a process leads to lactate accumulation in the tumor microenvironment (TME), further promoting cancer progression and inducing immunosuppression. Herein, functionalized dendrimer‐Cu(II) complexes (for short, D‐Cu(II)) as a nanocarrier, which enables a Fenton‐like reaction is developed to generate a large amount of hydroxyl radicals and shows a T1‐weighted magnetic resonance (MR) imaging performance. Importantly, the D‐Cu(II) allows efficient delivery of lactate oxidase (LOx) to cancer cells, directly downregulating the lactate levels. When combining with an immune activator of leukadherin‐1, the developed D‐Cu(II)/LOx complexes alleviate the symptoms of mouse leukemia. With a further coating of macrophage membranes, the generated D‐Cu(II)/LOx@M allows for effective blood‐brain barrier crossing to treat an orthotopic murine glioma model under the guidance of Cu(II)‐facilitated MR imaging. By integrating the LOx‐mediated lactate depletion with Cu(II)‐mediated chemodynamic therapy, the developed dendrimer nanomedicines improve the overall survival and antitumor immune responses of mice, and help to remodel the immunosuppressive TME in both cancer models, greatly sensitizing the treatment efficacy of immune activator. Such dendrimer technology may further be used for theranostics of other cancer types through lactate depletion‐enhanced combinational therapy. [ABSTRACT FROM AUTHOR]

The development of theragnostic nanosystems integrating FRET (fluorescence resonance energy transfer) imaging and chemodynamic therapy (CDT) for accurate diagnosis and effective treatment of lung tumors is still a big challenge. Herein, a peptide‐assembled 3D DNAzyme motor nanodevice is engineered for a self‐powered FRET amplifier profiling human neutrophil elastase (HNE) and self‐supplied H2O2 enhancing CDT. The nanodevice is prepared by depositing AuNPs on ZIF‐8, in which ZIF‐8 co‐loaded the lysosomal targeting peptide‐modified copper peroxides (PCPs) and hairpins (H1, H2, and H3), AuNPs are co‐labeled by DNAzyme‐peptide (DP) conjugate and H3. In the tumor micro‐environment, HNE driven 3D DNAzyme walker followed by an exponential amplification constructed by a synergistic cross‐activation between hybridization chain reaction and DNAzyme, generating a self‐powered FRET amplifier. The FRET amplifier specifically measures HNE with a sensitivity of 0.026 pM, and successfully images exogenous HNE in living cells and monitors HNE in mouse models. Moreover, the PCPs can target lysosomes, reducing lysosome escape. The self‐supplying H2O2 undertaken by PCPs improves the Cu (II)‐catalyzed Fenton‐like reaction, effectively causing cell apoptosis to inhibit tumor growth. Significantly, the nanodevice successfully screens inhibitors and discriminates the HNE level in normal and lung cancer tissues, suggesting that the nanodevice provides an effective tool for the diagnosis and treatment of lung tumors. [ABSTRACT FROM AUTHOR]

Background: Mn2+-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO3− level in the system. Although the physiological buffers (H2CO3/HCO3−) provide certain amounts of HCO3−, the acidity of the tumor microenvironment (TME) would seriously affect the HCO3− ionic equilibrium (H2CO3 ⇌ H+ + HCO3−). As a result, HCO3− level in the tumor region is actually insufficient to support effective Mn2+-mediated CDT. Results: In this study, a robust nanomodulator MnFe2O4@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO3− is presented to enhance therapeutic efficacy of Mn2+-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO3− ionic equilibrium to the positive direction, significantly boosting the generation of the HCO3−. Most importantly, such HCO3− supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe2O4 of PrSMZ to exert the remarkable antitumor effect on mouse models. Conclusions: This work addresses the challenge of insufficient HCO3− in the TME for Mn2+-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn2+-mediated CDT agents to treat cancer effectively. [ABSTRACT FROM AUTHOR]

Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8+ cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T 1 -weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T 1 -weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics. [Display omitted] [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT), designed to trigger a tumor-specific hydrogen peroxide (H2O2) reaction generating highly toxic hydroxyl radicals (·OH), has been investigated for cancer treatment. Unfortunately, the limited Fenton or Fenton-like reaction rate and the significant impact of excessive reducing glutathione (GSH) in the tumor microenvironment (TME) have severely compromised the effectiveness of CDT. To address this issue, we designed a dual-responsive nanoplatform utilizing a metal-polyphenol network (MPN) -coated multi-caged IrOx for efficient anti-tumor therapy in response to the acidic TME and intracellular excess of GSH, in which MPN composed of Fe3+ and tannic acid (TA). Initially, the acidic TME and intracellular excess of GSH lead to the degradation of the MPN shell, resulting in the release of Fe3+ and exposure of the IrOx core, facilitating the efficient dual-pathway CDT. Subsequently, the nanoplatform can mitigate the attenuation of CDT by consuming the excessive GSH within the tumor. Finally, the multi-caged structure of IrOx is advantageous for effectively implementing photothermal therapy (PTT) in coordination with CDT, further enhancing the therapeutic efficacy of tumors. Moreover, the outstanding Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) (T1/T2) multimodal imaging capabilities of IrOx@MPN enable early diagnosis and timely treatment. This work provides a typical example of the construction of a novel multifunctional platform for dual-responsive treatment of tumors. [ABSTRACT FROM AUTHOR]

Mild photothermal therapy (PTT) is an emerging and elegant approach with minimal adverse effects, demonstrating itself as an effective treatment for cancer. However, potential challenges may arise from the overexpression of heat shock protein 90 (HSP90) and the reliance on monotherapy. Here, a near‐infrared (NIR) light‐triggered MXene nanocomposite (FA@MXene/CuO2/GA) is developed to synergistically combine mild PTT and chemodynamic therapy (CDT) for remarkably effective tumor eradication without any notable tissue damage. Under the irradiation of NIR light, the nanocomposite effectively enhances the mild PTT by suppressing HSP90 expression through the release of gambogic acid (GA) due to the excellent photothermal performance of Ti3C2 MXene nanosheets as well as the tumor‐targeting ability and biocompatibility of the surface‐modified FA‐PEG‐SH. The copper‐based catalyst CuO2 in this system releases Cu2+ in an acid‐triggered manner within the tumor microenvironment, activating the Fenton‐like reaction to generate hydroxyl radicals, and the simultaneous production of H2O2 serves to alleviate the deficiency of endogenous H2O2 within the tumor. Overall, the current work showcases a remarkable synergistic anticancer effect of PTT and CDT, and also proposes new avenues for research in utilizing MXene nanomaterials for tumor treatment. [ABSTRACT FROM AUTHOR]

Schematic illustration showing the process of creating conductive MOF-coated 3D-printed scaffolds and their use in the treatment of osteosarcoma and for aiding in bone repair. [Display omitted] The integration of functional nanomaterials with tissue engineering scaffolds has emerged as a promising solution for simultaneously treating malignant bone tumors and repairing resected bone defects. However, achieving a uniform bioactive interface on 3D-printing polymer scaffolds with minimized microstructural heterogeneity remains a challenge. In this study, we report a facile metal-coordination self-assembly strategy for the surface engineering of 3D-printed polycaprolactone (PCL) scaffolds with nanostructured two-dimensional conjugated metal–organic frameworks (cMOFs) consisting of Cu ions and 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP). A tunable thickness of Cu-HHTP cMOF on PCL scaffolds was achieved via the alternative deposition of metal ions and HHTP. The resulting composite PCL@Cu-HHTP scaffolds not only demonstrated potent photothermal conversion capability for efficient OS ablation but also promoted the bone repair process by virtue of their cell-friendly hydrophilic interfaces. Therefore, the cMOF-engineered dual-functional 3D-printing scaffolds show promising potential for treating bone tumors by offering sequential anti-tumor effects and bone regeneration capabilities. This work also presents a new avenue for the interface engineering of bioactive scaffolds to meet multifaceted demands in osteosarcoma-related bone defects. [ABSTRACT FROM AUTHOR]

Immunotherapy offers a promising avenue for reducing tumor metastasis and recurrence but faces challenges from the tumor immunosuppressive microenvironment (TIME) and restricted antigen presentation. To address these challenges, this study have developed an innovative approach utilizing molybdenum (Mo)‐doped Prussian blue nanoparticles coated with a cancer cell membrane (CCM), referred to as PMo@CCM. This novel nanoplatform excels in performing photothermal therapy (PTT), while the Mo and Fe components effectively deplete glutathione (GSH) and generate reactive oxygen species (ROS), thereby significantly enhancing chemodynamic therapy (CDT) and remodeling the TIME. The synergistic PTT/CDT approach not only induces tumor immunogenic cell death (ICD) but also facilitates antigen presentation. The CCM coating further supplies antigens and prompts dendritic cell (DC) maturation. This comprehensive strategy markedly enhances the effectiveness of immunotherapy, as evidenced by a significant increase in T cell activation. Moreover, the use of programmed cell death protein 1 antibodies (anti PD‐1) effectively blocks the PD‐1 immune checkpoint pathway. RNA sequencing analysis has identified genes associated with the observed substantial reduction in tumor growth. In conclusion, the PMo@CCM nanoplatform enables homologously targeted tumor synergistic therapy, guided by photothermal and magnetic resonance imaging (PTI&MRI), significantly impeding the progression of both primary and metastatic tumors. [ABSTRACT FROM AUTHOR]

Developing novel nanomedicine formulations that successfully penetrate the blood-brain barrier (BBB) to treat and diagnose glioma effectively is still a significant obstacle. This study presents the development of polymer nanogels camouflaged with macrophage membranes. The nanogels are loaded with manganese dioxide (MnO 2) and carboplatin. They are designed for the treatment of glioma using a combination of chemotherapy and chemodynamic therapy (CDT). The precipitation polymerization process was used to create redox-responsive poly(caprolactone) (PCL) nanogels (NGs). These NGs were then loaded with MnO 2 and physically encapsulated with carboplatin. The resulting nanogels had an average diameter of 102.52 nm and were covered with macrophage membranes to provide excellent stability. The developed NGs exhibit redox and pH responsiveness, releasing carboplatin and Mn(II) in a controlled manner. NGs may effectively deplete glutathione (GSH) in the tumour milieu. The Mn(II) generated in this process enhances the effectiveness of the loaded carboplatin by exerting its chemotherapeutic action and promoting the formation of reactive oxygen species to improve the efficiency of CDT. The results of our study show a very efficient and promising nanomedicine platform for the treatment and diagnosis of glioma, a type of cancer. This platform is self-adaptive, cooperative, and based on NG technology. Furthermore, this platform can potentially be used for other challenging types of cancer. [Display omitted] • We developed polymeric nanogels camouflaged with macrophage membranes. • The nanogels are loaded with manganese dioxide (MnO 2) and carboplatin. • The precipitation polymerization was used to create redox-responsive nanogels. • NGs may effectively deplete glutathione (GSH) in the tumour milieu. • The Mn(II) enhances the chemotherapeutic action and promoting ROS. [ABSTRACT FROM AUTHOR]

Abstract Developing high-performance nanomedicines to enhance antitumor efficacy remains a hot point in the field of biomedicine. In this study, we designed a versatile nanocomposite (FeS₂@COF-HA/AIPH) integrating covalent organic frameworks (COF) functionalized with pyrite (FeS₂) for synergistic photothermal (PTT), chemodynamic (CDT), thermodynamic (TDT) therapies, and immunotherapy. The superior photothermal effects and catalytic capabilities of FeS₂@COF enabled a minimally invasive PTT/CDT combination. The nanoplatform, with its mesoporous structure, also served as a drug delivery system, encapsulating the thermos-decomposable initiator AIPH. The hyaluronic acid (HA) coating not only improved tumor-targeting efficiency but also prevented nonspecific AIPH release. Under near-infrared (NIR) irradiation, the localized hyperthermia triggered AIPH decomposition, generating toxic alkyl radicals (•R) for TDT, further enhancing CDT efficiency. The combination of PTT, CDT, TDT, and immunotherapy led to potent antitumor effects with minimal systemic toxicity, both in vitro and in vivo. Notably, the nanoplatform effectively reprogrammed tumor-associated macrophages (TAMs) from an M2 to M1 phenotype, boosting antitumor immunity. This multifunctional platform thus offers a promising strategy for integrated PTT, CDT, TDT, and immune activation in tumor therapy.

Qingcheng Song,1,2,* Yiran Zhang,3,* Hongzhi Hu,4,* Xuemei Yang,5 Xin Xing,1,2 Jianhua Wu,6 Yanbin Zhu,1,2 Yingze Zhang1,2 1Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Orthopaedic Institution of Hebei Province, Shijiazhuang, Hebei, People’s Republic of China; 3School of Medicine, Nankai University, Tianjin, People’s Republic of China; 4Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 5The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of China; 6The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingze Zhang; Yanbin Zhu, Email yzling_liu@163.com; 38600312@hebmu.edu.cnIntroduction: Ferroptosis-driven tumor ablation strategies based on nanotechnology could be achieved by elevating intracellular iron levels or inhibiting glutathione peroxidase 4 (GPX4) activity. However, the intracellular antioxidative defense mechanisms endow tumor cells with ferroptosis resistance capacity. The purpose of this study was to develop a synergistic therapeutic platform to enhance the efficacy of ferroptosis-based tumor therapy.Methods: In this study, a multifunctional nano-catalytic therapeutic platform (mFeB@PDA-FA) based on chemodynamic therapy (CDT) and photothermal therapy (PTT) was developed to effectively trigger ferroptosis in tumor. In our work, iron-based mesoporous Fe3O4 nanoparticles (mFe3O4 NPs) were employed for the encapsulation of L-buthionine sulfoximine (BSO), followed by the modification of folic acid-functionalized polydopamine (PDA) coating on the periphery. Then, the antitumor effect of mFeB@PDA-FA NPs was evaluated using Human OS cells (MNNG/HOS) and a subcutaneous xenograft model of osteosarcoma.Results: mFe3O4 harboring multivalent elements (Fe2+/3+) could catalyze hydrogen peroxide (H2O2) into highly cytotoxic ˙OH, while the tumor microenvironment (TME)-responsive released BSO molecules inhibit the biosynthesis of GSH, thus achieving the deactivation of GPX4 and the enhancement of ferroptosis. Moreover, thanks to the remarkable photothermal conversion performance of mFe3O4 and PDA shell, PTT further synergistically enhanced the efficacy of CDT and facilitated ferroptosis. Both in vivo and in vitro experiments confirmed that this synergistic therapy could achieve excellent tumor inhibition effects.Conclusion: The nanotherapeutic platform mFeB@PDA-FA could effectively disrupted the redox homeostasis in tumor cells for boosting ferroptosis through the combination of CDT, PTT and GSH elimination, which provided a new perspective for the treatment of ferroptosis sensitive tumors. Keywords: ferroptosis, chemodynamic therapy, photothermal therapy, Fenton reaction, BSO

Abstract Background Mn2+-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO3 − level in the system. Although the physiological buffers (H2CO3/HCO3 −) provide certain amounts of HCO3 −, the acidity of the tumor microenvironment (TME) would seriously affect the HCO3 − ionic equilibrium (H2CO3 ⇌ H+ + HCO3 −). As a result, HCO3 − level in the tumor region is actually insufficient to support effective Mn2+-mediated CDT. Results In this study, a robust nanomodulator MnFe2O4@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO3 − is presented to enhance therapeutic efficacy of Mn2+-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO3 − ionic equilibrium to the positive direction, significantly boosting the generation of the HCO3 −. Most importantly, such HCO3 − supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe2O4 of PrSMZ to exert the remarkable antitumor effect on mouse models. Conclusions This work addresses the challenge of insufficient HCO3 − in the TME for Mn2+-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn2+-mediated CDT agents to treat cancer effectively.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterised by a short survival period, high malignancy, strong invasiveness, and high rates of recurrence and metastasis. Due to its unique molecular phenotype, TNBC is insensitive to endocrine therapy or molecular targeted therapy. The conventional treatment approach involves systemic chemotherapy for overall management; however, adjuvant chemotherapy after surgery has shown poor efficacy as residual lesions can easily lead to tumour recurrence. Therefore, there is an urgent need to find more effective treatment strategies. Herein, we designed a gold nanocluster coated with a metal-phenol formaldehyde network structure (AuNCs@PDA-Mn) for tumour Photothermal therapy and chemodynamic therapy (PTT and CDT), which induces systemic immune responses to suppress tumour metastasis. Experimental results show that after continuous irradiation for 10 min under an 808 nm laser (1.0W/cm2), AuNCs@PDA-Mn not only exhibits better tumour inhibition both in vitro and in vivo but also triggers stronger immune effects systemically. Therefore, this combined PTT and CDT treatment approach has great potential and provides a clinically relevant and valuable option for triple-negative breast cancer.

The synthesized ADCuSi-FA, with its capabilities for GSH depletion and H 2 O 2 self-supply, functions as an intelligent theranostic nanoplatform for tumor-targeted PA imaging and photothermal/chemotherapy co-synergized CDT. [Display omitted] • A novel biodegradable reactive oxygen species nano-amplifier is proposed. • The CuS nanodot (1–2 nm) is the smallest one by far. • Intracellular redox homeostasis can be broken to improve chemodynamic therapy (CDT). • Chemotherapeutic effect is activated by complexing Cu2+ and disulfiram. • NIR-II photothermal therapy/chemotherapy can boost the CDT efficacy. Intracellular redox homeostasis and the type of exogenous Fenton reagent play crucial roles in determining the efficacy of chemodynamic therapy (CDT). Herein, we succeeded for the first time in preparing ultrasmall copper sulfide (CuS) nanodots (1–2 nm)-embedded hollow mesoporous organosilica nanoparticle (HMON), which served as an ideal nanocarrier to load both 3-amino-1,2,4-triazole (3-AT) and disulfiram (DSF) after folate-polyethylene glycol-silane (FA-PEG-Silane) modification. The as-prepared nanoplatform (3-AT/DSF@CuS/HMON-FA, denoted as ADCuSi-FA) was found to regulate intracellular redox homeostasis once internalized by 4T1 cells, showing rapid glutathione (GSH)-responsive 3-AT, DSF and Cu+ ions release. Specifically, 3-AT restrained the endogenous hydrogen peroxide (H 2 O 2) consumption by suppressing catalase (CAT) activity, thereby augmenting hydroxyl radical (OH) generation via Cu+-based Fenton-like reaction. DSF, upon complexation with Cu2+, exhibited enhanced chemotherapeutic efficacy, while the by-product Cu+ ions further boosted the efficacy of CDT. Additionally, CuS nanodots enabled near-infrared-II (NIR-II) photothermal therapy (PTT) and facilitated photoacoustic (PA) imaging, with the ensuing hyperthermia expediting the CDT process. As expected, the tumor growth was dramatically inhibited with PTT/chemotherapy co-synergized CDT. This work offers an innovative paradigm for cooperative cancer treatment as well as new insights into the fabrication of biodegradable inorganic/organic hybrid materials. [ABSTRACT FROM AUTHOR]

A novel multifunctional nanozyme IMMMF loading ICG and oxidative phosphorylation inhibitor metformin (Met) inside hollow MnO 2 nanoparticle with metal-polyphenol networks (MPNs) coatings between Fe3+ and folic acid (FA) immobilized tannic acid was constructed to achieve O 2 -generation/O 2 -economization dually enhanced SDT/CDT synergistic antitumor therapy. [Display omitted] As an emerging therapeutic method, the application of sonodynamic therapy (SDT) is hindered by its intrinsic unsatisfactory efficiency, the tumor hypoxia and low tumor specificity. Here, we reported the design of a tumor-targeting multifunctional nanodrug for O 2 -generation/O 2 -economization dually enhanced SDT/chemodynamic therapy (CDT) combination therapy. After the co-encapsulation of sonosensitizer indocyanine green (ICG) and oxidative phosphorylation inhibitor metformin (Met) into hollow MnO 2 (H-MnO 2) nanoparticles, ICG/Met@H-MnO 2 @MPN-FA (IMMMF) was conveniently prepared through the formation of metal–phenolic networks (MPNs) between Fe3+ and folic acid (FA) immobilized tannic acid (TA, TA-FA) onto its surface. In vitro experiments indicated its selective uptake by 4T1 cells via the specific folate receptors-FA interactions. Responding to glutathione (GSH) and the acidic environment, the decomposition of IMMMF led to the release of Mn2+ and Fe2+ for enhanced CDT, and ICG for SDT. Furthermore, Met was continuously released to reduce O 2 consumption for enhanced SDT. More importantly, IMMMF catalyzed the endogenous H 2 O 2 into O 2 for further enhanced SDT. Expectedly, both in vitro and in vivo antitumor assays confirmed its satisfactory therapeutic efficiency via CDT/SDT synergistic therapy. Hence, this intelligent sonocatalytic nanoagent emerges as a promising candidate for CDT-enhanced SDT, which also provides a novel strategy for dually alleviating tumor hypoxia with better therapy. [ABSTRACT FROM AUTHOR]

Metal-phenolic networks (MPNs)-crosslinked hyaluronic acid (HA) nanogels are fabricated for co-delivery of Fe2+ and dihydroartemisinin (DHA), enabling photothermal/DHA dually-enhanced chemodynamic therapy for treating biofilm-associated infections. [Display omitted] Chemodynamic therapy (CDT) is emerging as a promising treatment for biofilm infections. However, its effectiveness is significantly hindered by several factors: the body's stable temperature, a limited supply of Fe2+ ions, and inadequate endogenous levels of H 2 O 2 at the infection sites. Herin, our study introduces MPN-crosslinked hyaluronic acid (HA) nanogels as an effective strategy for treating biofilm-associated infections. The DHA@HA-TA/Fe (DHTF) nanogel is synthesized through the coordination reaction between Fe2+ ions and tannic acid (TA)-modified HA, with dihydroartemisinin (DHA) encapsulated within the structure. DHTF exhibits pH-/hyaluronidase-responsiveness in the biofilm infection microenvironment, enabling sustained release of DHA as a substitute for H 2 O 2 and Fe2+ for CDT. The incorporation of Fe2+/TA-based MPN and DHA within the nanogels enables photothermal/DHA dually-enhanced CDT, facilitating efficient disruption of biofilm matrices and bacterial eradication through boosting reactive oxygen species production. In vivo studies demonstrate that DHTF exhibit prolonged retention within biofilms. This ensures a sustained release of therapeutic agents and continuous anti-biofilm activity. Eventually, both in vitro and in vivo evaluations consistently confirm the significant anti-biofilm capacity of DHTF. Our findings highlight the potential of DHTF as a promising nanomedicine for biofilm-related infections, offering efficient treatment strategies that could improve clinical management of these challenging conditions. [ABSTRACT FROM AUTHOR]

2D chitosan modified Mo x W 1−x Se 2 transformed conformational nanoarchitectonics loaded with chemotherapeutic drug mitoxantrone was utilized to explore the synergistic therapeutic effects of triple PTT/CDT/CT, thereby achieving the personalised therapy of breast carcinoma. [Display omitted] Two-dimensional transition metal dichalcogenides (TMDCs) exhibit promising photothermal therapy (PTT) and chemodynamic therapy (CDT) for anti-tumour treatment. Herein, we proposed an engineering strategy to regulate the lattice structure of tungsten-doped molybdenum selenide (Mo x W 1−x Se 2) transformed conformational nanoarchitectonics using a microwave-assisted solvothermal method for enhancing peroxidase (POD)-like catalytic performance by adjusting the ratio of molybdenum (Mo) and tungsten (W). Furthermore, the optimised Mo 0.8 W 0.2 Se 2 nanoflakes surface was modified with chitosan (CHI) for improved biocompatibility and nanocatalytic efficacy, then the obtained CHI-Mo 0.8 W 0.2 Se 2 subsequently loaded the chemotherapeutic drug mitoxantrone (MTO) for enhanced 4 T1 cells killing ability, shortly denoted as CHI-Mo 0.8 W 0.2 Se 2 -MTO for PTT-augmented CDT and chemotherapy (CT). A series of performance validations successfully showed that electrons tend to transfer from W to Mo in CHI-Mo 0.8 W 0.2 Se 2 , which resulted in superior POD-like activity (K m = 0.038 mM) of CHI-Mo 0.8 W 0.2 Se 2 compared with that of horseradish peroxidase. Furthermore, CHI-Mo 0.8 W 0.2 Se 2 -MTO with excellent photothermal conversion efficiency (PCE=63.2 %) in the near-infrared (NIR) region could further promote endogenous •OH generation and MTO controlled release within solid tumours. In vivo studies confirmed the successful achievement of synergistic therapeutic effects (tumour inhibition rate of over 90 %) with minimised side effects. Versatile therapeutic nanoagents hold great potential for personalised therapy of breast cancer and will find their way to the pharmaceutical field. [ABSTRACT FROM AUTHOR]

[Display omitted] Chemodynamic therapy (CDT) and photothermal therapy (PTT) have both demonstrated considerable efficacy in the tumor treatment individually, owing to their non-invasive nature and excellent selectivity. However, due to the propensity of tumors for metastasis and recurrence, a singular therapeutic approach falls short of achieving optimal treatment outcomes. Polydopamine (PDA) has excellent photothermal conversion ability and polyoxometalates (POMs) possess diverse enzymatic activities. Here, we synthesized PDA@POM nanospheres comprising polydopamine-coated Tungsten-based polyoxometalate (W-POM). These nanospheres leverage dual enzymatic activities that synergistically enhance both chemodynamic and photothermal therapies for tumor treatment. The PDA-mediated PTT effect enables precise tumor cell destruction, while the W-POM nanozymes catalyzes the generation of highly toxic reactive oxygen species (ROS) from hydrogen peroxide within tumor cells through a Fenton-like reaction, which mitigates tumor hypoxia and induces tumor cell death. This synergistic photothermal catalytic therapy shows enhanced efficacy in tumor suppression, providing a promising new approach for tumor treatment. [ABSTRACT FROM AUTHOR]

A silica delivery platform loaded with autophagy-inducing reagents and iron-based Fenton reagents was utilized to explore a novel strategy leveraging autophagy to reduce tumor acidity, thereby enhancing the effectiveness of CDT. [Display omitted] Iron-based chemodynamic therapy (CDT) exhibits commendable biocompatibility and selectivity, but its efficacy is constrained by the intracellular pH of tumors. To overcome this obstacle, we constructed a silica delivery platform loaded with autophagy-inducing reagents (rapamycin, RAPA) and iron-based Fenton reagents (Fe 3 O 4). This platform was utilized to explore a novel strategy that leverages autophagy to decrease tumor acidity, consequently boosting the effectiveness of CDT. Both in vitro and in vivo experiments revealed that RAPA prompted the generation of acidic organelles (e.g., autophagic vacuoles and autophagosomes), effectively changing the intracellular pH in the tumor microenvironment. Furthermore, RAPA-induced tumor acidification significantly amplified the efficacy of Fe 3 O 4 -based Fenton reactions, consequently increasing the effectiveness of Fe 3 O 4 -based CDT. This innovative approach, which leverages the interplay between autophagy induction and iron-based CDT, shows promise in overcoming the limitations posed by tumor pH, thus offering a more efficient approach to tumor treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] • CoNiCoNC can catalyze the self-supply of H 2 O 2 from glucose and lactate, alleviating low H 2 O 2 levels in the tumor TME. • CoNiCoNC has the ability to catalyze the production of O2 from H 2 O 2 to alleviate hypoxia in tumor TME. • CoNiCoNC has GSH oxidase-like activity and causes cellular ferroptosis. • CoNiCoNC can catalyze the production of large amounts of ROS by H 2 O 2 in the tumor microenvironment and damage tumor cells. The effectiveness of chemokinetic therapy nanozymes is severely constrained because of the low H 2 O 2 levels in the tumor microenvironment. Unlike other self-produced H 2 O 2 nanozymes, the N -CNTs-encapsulated CoNi alloy (CoNiCoNC) with glucose oxidase and lactate oxidase activities has two ways to produce H 2 O 2. It can facilitate the transformation of glucose and lactic acid into H 2 O 2 simultaneously. First, the H 2 O 2 generation pathway is favorable for aggravating energy metabolism. Second, some produced H 2 O 2 can be decomposed by CoNiCoNC to H 2 O and O 2 with the 4e − pathway to alleviate the TME hypoxia. Third, H 2 O 2 can be catalyzed to form OH to enhance reactive oxygen species (ROS) content. Through proteomic analysis, nanozymes substantially impact the metabolic pathways of cancer cells because of their aggravating energy metabolism. The high levels of ROS can cause mitochondrial lipid peroxidation and cellular ferroptosis. Consequently, the two-way H 2 O 2 -selective nanoenzymatic platform realizes the synergistic effect of starvation therapy and chemokinetics. [ABSTRACT FROM AUTHOR]

[Display omitted] • A nanoplatform capable of both self-supplying H 2 O 2 and generating NO is designed to enhance the effectiveness of chemodynamic therapy for biofilm eradication. • The nanoplatform can respond to the acidic microenvironment within biofilms to trigger a cascade of reactions that produce reactive species such as NO, hydroxyl radicals, and peroxynitrite. • The nanoplatform shows remarkable antibiofilm efficacy by dispersing the biofilm and reducing bacterial viability. Bacterial biofilms present a profound challenge to global public health, often resulting in persistent and recurrent infections that resist treatment. Chemodynamic therapy (CDT), leveraging the conversion of hydrogen peroxide (H 2 O 2) to highly reactive hydroxyl radicals (•OH), has shown potential as an antibacterial approach. Nonetheless, CDT struggles to eliminate biofilms due to limited endogenous H 2 O 2 and the protective extracellular polymeric substances (EPS) within biofilms. This study introduces a multifunctional nanoplatform designed to self-supply H 2 O 2 and generate nitric oxide (NO) to overcome these hurdles. The nanoplatform comprises calcium peroxide (CaO 2) for sustained H 2 O 2 production, a copper-based metal–organic framework (HKUST-1) encapsulating CaO 2 , and l -arginine (l -Arg) as a natural NO donor. When exposed to the acidic microenvironment within biofilms, the HKUST-1 layer decomposes, releasing Cu2+ ions and l -Arg, and exposing the CaO 2 core to initiate a cascade of reactions producing reactive species such as H 2 O 2 , •OH, and superoxide anions (•O 2 –). Subsequently, H 2 O 2 catalyzes l -Arg to produce NO, which disperses the biofilm and reacts with •O 2 – to form peroxynitrite, synergistically eradicating bacteria with •OH. In vitro assays demonstrated the nanoplatform's remarkable antibiofilm efficacy against both Gram-positive Methicillin-resistant Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa , significantly reducing bacterial viability and EPS content. In vivo mouse model experiments validated the nanoplatform's effectiveness in eliminating biofilms and promoting infected wound healing without adverse effects. This study represents a breakthrough in overcoming traditional CDT limitations by integrating self-supplied H 2 O 2 with NO's biofilm-disrupting capabilities, offering a promising therapeutic strategy for biofilm-associated infection. [ABSTRACT FROM AUTHOR]

Abstract Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment. Graphical abstract

Ferroptosis is a recently discovered pathway for regulated cell death pathway. However, its efficacy is affected by limited iron content and intracellular ion homeostasis. Here, we designed a metal-organic framework (MOF)-based nanoplatform that incorporates calcium peroxide (CaO2) and oridonin (ORI). This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis, thereby enhancing ferroptosis therapy. Fused cell membranes (FM) were used to modify nanoparticles (ORI@CaO2@Fe-TCPP, NPs) to produce FM@ORI@CaO2@Fe-TCPP (FM@NPs). The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously, working in tandem with Fe3+ to induce ferroptosis. Photodynamic therapy (PDT) guided by porphyrin (TCPP) significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species (ROS). This self-amplifying strategy promoted robust ferroptosis, which could work synergistically with FM-mediated immunotherapy. In vivo experiments showed that FM@NPs inhibited 91.57% of melanoma cells within six days, a rate 5.6 times higher than chemotherapy alone. FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity. Thus, this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment.

Once bone metastasis occurs in lung cancer, the efficiency of treatment can be greatly reduced. Current mainstream treatments are focused on inhibiting cancer cell growth and preventing bone destruction. Microwave ablation (MWA) has been used to treat bone tumors. However, MWA may damage the surrounding normal tissues. Therefore, it could be beneficial to develop a nanocarrier combined with microwave to treat bone metastasis. Herein, a microwave-responsive nanoplatform (MgFe2O4@ZOL) was constructed. MgFe2O4@ZOL NPs release the cargos of Fe3+, Mg2+ and zoledronic acid (ZOL) in the acidic tumor microenvironment (TME). Fe3+ can deplete intracellular glutathione (GSH) and catalyze H2O2 to generate •OH, resulting in chemodynamic therapy (CDT). In addition, the microwave can significantly enhance the production of reactive oxygen species (ROS), thereby enabling the effective implementation of microwave dynamic therapy (MDT). Moreover, Mg2+ and ZOL promote osteoblast differentiation. In addition, MgFe2O4@ZOL NPs could target and selectively heat tumor tissue and enhance the effect of microwave thermal therapy (MTT). Both in vitro and in vivo experiments revealed that synergistic targeting, GSH depletion-enhanced CDT, MDT, and selective MTT exhibited significant antitumor efficacy and bone repair. This multimodal combination therapy provides a promising strategy for the treatment of bone metastasis in lung cancer patients.

Jing Kong,1,* Jiabin Lai,2– 4,* Min Wang,5,* Yi Xie,1 Haifei He,6 Jiayu Gu,7 Tao Pan,6 Zhiqiang Lu,8 Lifeng Jiang3,4 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Orthopedic Research Institute of Zhejiang University, Hangzhou, People’s Republic of China; 4Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, People’s Republic of China; 5Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University & Jiangsu Province Hospital, Nanjing, People’s Republic of China; 6Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 7Jiangsu Institute of Metrology, Nanjing, People’s Republic of China; 8Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lifeng Jiang; Zhiqiang Lu, Email jianglifeng@zju.edu.cn; taiyi1981@126.comBackground: Chemodynamic therapy (CDT) faces challenges of low catalytic ion efficiency and ROS production. We developed a ROS nano-bomb, Cu/ZIF-8@GA-Fe, to address these issues.Methods: The nano-bomb was synthesized by doping copper into ZIF-8 and assembling Fe3+ and gallic acid (GA). It was tested for reactive oxygen species (ROS) generation in acidic conditions and its photothermal properties.Results: In an acidic micro environment, Cu/ZIF-8@GA-Fe effectively released Fe3+ and Cu2+, depleting GSH and generating ROS. The GA-Fe coating provided photothermal heat and was used to enhance Fenton reactions via dual ions for increasing ROS production. In vivo and in vitro experiments, Cu/ZIF-8@GA-Fe inhibited tumor growth with minimal side effects.Conclusion: Cu/ZIF-8@GA-Fe shows promise for safe and effective CDT, offering a synergistic approach to tumor therapy.Keywords: reactive oxygen species, nano-bomb, combination therapy, chemodynamic therapy, photothermal therapy

Abstract With breast cancer emerging as a pressing global health challenge, characterized by escalating incidence rates and geographical disparities, there is a critical need for innovative therapeutic strategies. This comprehensive research navigates the landscape of nanomedicine, specifically focusing on the potential of magnetic nanoparticles (MNPs), with magnetite (Fe3O4) taking center stage. MNPs, encapsulated in biocompatible polymers like silica known as magnetic silica nanoparticles (MSN), are augmented with phosphotungstate (PTA) for enhanced chemodynamic therapy (CDT). PTA is recognized for its dual role as a natural chelator and electron shuttle, expediting electron transfer from ferric (Fe3+) to ferrous (Fe2+) ions within nanoparticles. Additionally, protein-based charge-reversal nanocarriers like silk sericin and gluten are introduced to encapsulate (MSN-PTA) nanoparticles, offering a dynamic facet to drug delivery systems for potential revolutionization of breast cancer therapy. This study successfully formulates and characterizes protein-coated nanocapsules, specifically MSN-PTA-SER, and MSN-PTA-GLU, with optimal physicochemical attributes for drug delivery applications. The careful optimization of sericin and gluten concentrations results in finely tuned nanoparticles, showcasing uniform size, enhanced negative zeta potential, and remarkable stability. Various analyses, from Dynamic Light Scattering (DLS) and scanning electron microscopy (SEM) to transmission electron microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR), X-Ray diffraction analysis (XRD), and Thermogravimetric analysis (TGA), provide insights into structural integrity and surface modifications. Vibrating Sample Magnetometer (VSM) analysis underscores superparamagnetic behavior, positioning these nanocapsules as promising candidates for targeted drug delivery. In vitro evaluations demonstrate dose-dependent inhibition of cell viability in MCF-7 and Zr-75–1 breast cancer cells, emphasizing the therapeutic potential of MSN-PTA-SER and MSN-PTA-GLU. The interplay of surface charge and pH-dependent cellular uptake highlights the robust stability and versatility of these nanocarriers in tumor microenvironment, paving the way for advancements in targeted drug delivery and personalized nanomedicine. This comparative analysis explores the suitability of silk sericin and gluten, unraveling a promising avenue for the development of advanced, targeted, and efficient breast cancer treatments.

Abstract It is of great significance to develop a novel approach to treat bacterial infections, as the frequent misuse of antibiotics leads to the serious problem of bacterial resistance. This study proposed antibiotic-free antibacterial nanoparticles for eliminating methicillin-resistant Staphylococcus aureus (MRSA) based on a multi-model synergistic antibacterial ability of chemodynamic therapy (CDT), photothermal effect, and innate immunomodulation. Specifically, a polydopamine (PDA) layer coated and Ag nanoparticles loaded core-shell structure Fe3O4 nanoparticles (Fe3O4@PDA-Ag) is prepared. The Fe3O4 catalyzes H2O2 present in acidic microenvironment of bacterial infection into more toxic reactive oxygen species (ROS) and synergizes with the released Ag ions to exert a stronger bactericidal capacity, which can be augmented by photothermal action of PDA triggered by near-infrared light and loosen the biofilm by photothermal action to promote the penetration of ROS and Ag ion into the biofilm, result in disrupting biofilm structure along with killing encapsulated bacteria. Furthermore, Fe3O4@PDA-Ag exerts indirect antibacterial effects by promoting M1 macrophage polarizing. Animal models demonstrated that Fe3O4@PDA-Ag effectively controlled MRSA-induced infections through photothermal enhanced CDT, Ag+ releasing, and macrophage-mediated bactericidal properties. The acid-triggered antibacterial nanoparticles are expected to combat drug-resistant bacteria infection. Graphical abstract

Combining photodynamic therapy (PDT) with chemodynamic therapy (CDT) has been proven to be a promising strategy to improve the treatment efficiency of cancer, because of the synergistic therapeutic effect arising between the two modalities. Herein, we report an inorganic nanoagent based on ternary NiCoTi-layered double hydroxide (NiCoTi-LDH) nanosheets to realize highly efficient photodynamic/chemodynamic synergistic therapy. The NiCoTi-LDH nanosheets exhibit oxygen vacancy-promoted electron-hole separation and photogenerated hole-induced O2-independent reactive oxygen species (ROS) generation under acidic circumstances, realizing in situ pH-responsive PDT. Moreover, due to the effective conversion between Co3+ and Co2+ caused by photogenerated electrons, the NiCoTi-LDH nanosheets catalyze the release of hydroxyl radicals (·OH) from H2O2 through Fenton reactions, resulting in CDT. Laser irradiation enhances the catalyzed ability of the NiCoTi-LDH nanosheets to promote the ROS generation, resulting in a better performance than TiO2 nanoparticles at pH 6.5. In vitro and in vivo experimental results show conclusively that NiCoTi-LDH nanosheets plus irradiation lead to efficient cell apoptosis and significant inhibition of tumor growth. This study reports a new pH-responsive inorganic nanoagent with oxygen vacancy-promoted photodynamic/chemodynamic synergistic performance, offering a potentially appealing clinical strategy for selective tumor elimination.

The problem of antimicrobial resistance (AMR) caused by the abuse of antibiotics is becoming serious. The development of antibacterial materials with synergistic efficiency and treatment of deep tissue/organ infections is imminent. Herein, synergistic antibacterial nanoparticles (MPH NPs) are prepared by loading antibacterial peptide polymyxin B (PMB) on Fe‐based MOF (MIL‐100) with hyaluronic acid (HA) modification. MPH NPs exerts antibacterial effects by chemodynamic therapy (CDT) and the release of PMB. MPH NPs have broad‐spectrum antibacterial properties on Gram‐negative bacteria (E. coli, 100%), Gram‐positive bacteria (S. aureus, 98.5 %), and MRSA (98.4%). Importantly, MPH NPs not only promote the healing of infected wounds but also target lungs to accomplish organ infection therapy. Therefore, this study provides a new strategy for designing a synergetic anti‐AMR bacteria system and the function for deep tissue/organ infection therapy in the future. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) is a novel tumor treatment method by using hydroxyl radicals (•OH) to kill cancer cells. However, its therapeutic effects are strictly confined by the short lifespan of •OH and reduced •OH generation speed. Herein, an effective CDT is achieved by both improving •OH lifetime and long‐lasting generating •OH through intraparticle electron transfer within heterogeneous nanoparticles (NPs). These heterogeneous NPs are composed of evenly distributed Cu and Fe3O4 (CFO NPs) with large interaction interfaces, and electrons tend to transfer from Cu to Fe3O4 for the appearance of ≡Cu2+ and increase in ≡Fe2+. The generated ≡Cu2+ can interact with GSH, which prolongs the lifespan of •OH, produces ≡Cu+ for higher speed •OH generation with H2O2, and induces cell ferroptosis for tumor therapy. The improved ≡Fe2+ can also improve the •OH release under H2O2 until Cu is depleted. As a result, a sustainable •OH generation is achieved to promote cell apoptosis for effective tumor therapy. Since H2O2 and GSH are only overexpressed at tumor, and CFO NPs can degrade in the tumor microenvironment, these NPs are with high biosafety and can be metabolized by urine. This work provides a novel biomaterial for effective cancer CDT through intraparticle electron transfer. [ABSTRACT FROM AUTHOR]

We have developed a new type of nanoparticles with potent antitumor activity photoactivatable via the combination of molecular photoswitching of spiropyran (SP) and enzymatic reaction of glucose oxidase (GOx). As two key processes involved therein, Fe(III)‐to‐Fe(II) photoreduction in Fe(III) metal–organic frameworks (MOFs) brings about the release of free Fe2+/Fe3+ while the photoswitching of SP to merocyanine (MC) unlocks the enzymatic activity of GOx that was pre‐passivated by SP. The release of free Fe3+ boosts its hydrolysis and therefore enables the acidification of microenvironment, which is further reinforced by one of the products of the GOx‐mediated glucose oxidation reaction, gluconic acid (GlcA). Based on the generation of Fe2+ and acidic milieu together with another product of the oxidation reaction, hydrogen peroxide (H2O2), these two processes jointly present triple enabling factors for generating lethal hydroxyl radicals (⋅OH) species via Fenton reactions and therefore oxidative stress capable of inhibiting tumor. The antitumor potency of such nanoparticle is verified in tumor‐bearing model mice in vivo, proclaiming its potential as a potent and safe agent based on the unique mechanism of optically manipulating enzyme activity for synergistic antitumor therapeutics with high spatial precision, enhanced efficacy and minimized side effects. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (⋅OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY‐ferrocene conjugate with a balanced 1O2 and ⋅OH generation capacity, which can serve as a high‐efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as‐prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY‐ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Redox nanozymes offer an appealing reactive oxygen species (ROS)‐based antibacterial strategy via disrupting intracellular homeostasis, however, they still face many obstacles such as low enzymic activity and irreversible loss of catalytic active center. Meanwhile, the antioxidant glutathione (GSH) overexpressed in infected sites would limit the therapy efficiency. Herein, we develop a multifunctional nanozyme based on copper(I) (Cu+) ion doped MoO3–x (Cu+‐MoO3–x) by a simple yet efficient oxygen vacancy‐reduced strategy without any pretreatment or additional agents. The resultant Cu+‐MoO3–x hybrid possesses enhanced peroxidase‐like (POD‐like) activity, rapid GSH‐depleting function and biodegradable ability. It can achieve highly efficient elimination of Pseudomonas aeruginosa (P. aeruginosa) via disrupting cellular redox balance. More intriguingly, GSH‐depleting redox reaction between Cu+‐MoO3–x and GSH could translate Mo6+ into Mo5+, thereby leading to partial recovery of POD‐like activity of Cu+‐MoO3–x hybrid for continuous ∙OH generation. In vitro and in vivo experiments demonstrated that Cu+‐MoO3–x hybrid had stronger antibacterial property compared to MoO3–x by rapid GSH consumption and plentiful ∙OH generation without providing extra H2O2, as well as neglective toxicity to healthy organs. In view of its remarkable enzymic activity and good biosafety, the developed Cu+‐MoO3–x redox nanozyme can be used as a promising antimicrobial for P. aeruginosa infection. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment. [ABSTRACT FROM AUTHOR]

Nanozymes have obvious advantages in improving the efficiency of cancer treatment. However, due to the lack of tissue specificity, low catalytic efficiency, and so on, their clinical applications are limited. Herein, the nanoplatform CeO2@ICG@GOx@HA (CIGH) with self‐accelerated cascade reactions is constructed. The as‐prepared nanozyme shows the superior oxidase (OXD)‐like, superoxide dismutase (SOD)‐like, catalase (CAT)‐like and peroxidase (POD)‐like activities. At the same time, under 808 nm near‐infrared (NIR) irradiation, the photodynamic and photothermal capabilities are also significantly enhanced due to the presence of indocyanine green (ICG). We demonstrate that the nanozyme CIGH can efficiently accumulate in the tumor and exhibit amplified cascade antitumor effects with negligible systemic toxicity through the combination of photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT) and starvation therapy. The nanozyme prepared in this study provides a promising candidate for catalytic nanomedicines for efficient tumor therapy. [ABSTRACT FROM AUTHOR]

Ferroptosis is a recently discovered pathway for regulated cell death pathway. However, its efficacy is affected by limited iron content and intracellular ion homeostasis. Here, we designed a metal-organic framework (MOF)-based nanoplatform that incorporates calcium peroxide (CaO 2) and oridonin (ORI). This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis, thereby enhancing ferroptosis therapy. Fused cell membranes (FM) were used to modify nanoparticles (ORI@CaO 2 @Fe-TCPP, NPs) to produce FM@ORI@CaO 2 @Fe-TCPP (FM@NPs). The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously, working in tandem with Fe3+ to induce ferroptosis. Photodynamic therapy (PDT) guided by porphyrin (TCPP) significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species (ROS). This self-amplifying strategy promoted robust ferroptosis, which could work synergistically with FM-mediated immunotherapy. In vivo experiments showed that FM@NPs inhibited 91.57% of melanoma cells within six days, a rate 5.6 times higher than chemotherapy alone. FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity. Thus, this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment. An iron-based metal-organic framework nanoplatform for enhanced ferroptosis therapy as a comprehensive antitumor strategy was reported. [Display omitted] [ABSTRACT FROM AUTHOR]

The effectiveness of tumor treatment using reactive oxygen species as the primary therapeutic medium is hindered by limitations of tumor microenvironment (TME), such as intrinsic hypoxia in photodynamic therapy (PDT) and overproduction of reducing glutathione (GSH) in chemodynamic therapy (CDT). Herein, we fabricate metal-polyphenol self-assembled nanodots (Fe@BDP NDs) guided by second near-infrared (NIR-II) fluorescence imaging. The Fe@BDP NDs are designed for synergistic combination of type-I PDT and CDT-amplified ferroptosis. In a mildly acidic TME, Fe@BDP NDs demonstrate great Fenton activity, leading to the generation of highly toxic hydroxyl radicals from overproduced hydrogen peroxide in tumor cells. Furthermore, Fe@BDP NDs show favorable efficacy in type-I PDT, even in tolerating tumor hypoxia, generating active superoxide anion upon exposure to 808 nm laser irradiation. The significant efficiency in reactive oxygen species (ROS) products results in the oxidation of sensitive polyunsaturated fatty acids, accelerating lethal lipid peroxidation (LPO) bioprocess. Additionally, Fe@BDP NDs illustrate an outstanding capability for GSH depletion, causing the inactivation of glutathione peroxidase 4 and further promoting lethal LPO. The synergistic type-I photodynamic and chemodynamic cytotoxicity effectively trigger irreversible ferroptosis by disrupting the intracellular redox homeostasis. Moreover, Fe@BDP NDs demonstrate charming NIR-II fluorescence imaging capability and effectively accumulated at the tumor site, visualizing the distribution of Fe@BDP NDs and the treatment process. The chemo/photo-dynamic-amplified ferroptotic efficacy of Fe@BDP NDs was evidenced both in vitro and in vivo. This study presents a compelling approach to intensify ferroptosis via visualized CDT and PDT. In this study, we detailed the fabrication of metal-polyphenol self-assembled nanodots (Fe@BDP NDs) guided by second near-infrared (NIR-II) fluorescence imaging, aiming to intensify ferroptosis via the synergistic combination of type-I PDT and CDT. In a mildly acidic TME, Fe@BDP NDs exhibited significant Fenton activity, resulting in the generation of highly toxic •OH from overproduced H 2 O 2 in tumor cells. Fe@BDP NDs possessed a remarkable capability for GSH depletion, resulting in the inactivation of glutathione peroxidase 4 (GPX4) and further accelerating lethal LPO. This study presented a compelling approach to intensify ferroptosis via visualized CDT and PDT. [Display omitted] [ABSTRACT FROM AUTHOR]

Nanofiber (NF) membrane systems that can provide cascade catalytic reaction and ferroptosis induction were developed for oral cancer therapy. Glucose oxidase (GOx) and aminoferrocene (AF) were introduced into the NF system for glucose deprivation/H2O2 generation and OH radical generation, respectively. GOx offers starvation therapy and AF (including iron) provides chemodynamic therapy/ferroptosis for combating oral cancer. GOx (water-soluble) and AF (poorly water-soluble) molecules were successfully entrapped in the NF membrane via an electrospinning process. GOx and AF were incorporated into the polyvinyl alcohol (PVA)-based NF, resulting in PVA/GOx/AF NF with fast disintegration and immediate drug-release properties. In oral squamous cell carcinoma (YD-9 cells), the PVA/GOx/AF NF group exhibited higher cytotoxicity, antiproliferation potential, cellular ROS level, apoptosis induction, lipid ROS level, and malondialdehyde level compared to the other NF groups. The electrospun PVA/GOx/AF NF can be directly applied to oral cancer without causing pain, offering starvation/chemodynamic therapy and ferroptosis induction. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) has emerged as a novel approach to overcome cancer resistance and enhance anticancer efficacy. Despite the considerable effort devoted to current chemodynamic therapeutic agents, developing efficient delivery systems to induce ferroptosis remains demanding due to their limited efficacy and lack of selectivity. Herein, an iron‐based single‐atom upconversion photocatalyst (UmFe‐OA@hPM) mimicking natural horseradish peroxidases has been developed. This nanoformulation not only targets tumors via the existence of a hybrid platelet membrane (hPM) coating but also generates excessive hydroxyl radicals in response to both tumor microenvironment and external laser irradiation. This nanoenzyme overcomes the low tissue penetration of UV light, which sensitizes the iron‐doped graphitic carbon nitride network, attributed to the unique anti‐Stokes shift from infrared to UV displayed by upconversion nanoparticles. Together with an increase in intracellular polyunsaturated fatty acid accumulation induced by oleanolic acid (OA), lipid peroxidation is significantly elevated, leading to the enhancement of CDT. UmFe‐OA@hPM is demonstrated to induce significant ferroptosis in vitro, superior antitumor efficacy in breast cancer mouse models, and suppression of metastasis status when incorporated with an immune checkpoint blockade. These findings provide a potential strategy for developing a precisely controlled CDT to deal with aggressive cancers, especially in combination with immunotherapy. [ABSTRACT FROM AUTHOR]

Bacteria‐initiated cancer therapy has been demonstrated high therapeutic efficacy against cancer. However, the undesired therapeutic efficacy and induced systematic inflammation storm compromise the therapeutic effect and outcome. Herein, a thermally‐activated living nanomedicine composed of reactive biohybrid (designated as Sa@FeS) is rationally designed and engineered for enhancing hydrogen sulfide (H2S)‐combined chemodynamic oncotherapy by biomineralizing ferrous sulfide nanoparticles (FeS NPs) onto the surface of a Salmonella typhimurium strain (Sa) without reducing bacterial activity. Ascribed to the deep penetration capability of Sa, FeS NPs facilitate photothermally‐enhanced catalytic Fenton reaction of decomposing endogenous H2O2 into cytotoxic hydroxyl radicals deep in tumor tissues upon near infrared irradiation. Meanwhile, Sa bacteria maintain sustained H2S release within tumor for achieving H2S‐induced intracellular acidosis that favors the generation of reactive oxygen species synergistically. Of note, the thermally‐triggered all‐in‐one strategy effectively inhibits bacterial viability, thus reducing the risk of systematic inflammation storm and ensuring biosafety. Therefore, the engineered nano‐bacteria living system exerts the thermally‐enhanced nanocatalytic and gas therapies to effectively eradicate tumors, providing a distinct paradigm for the combination of synthetic biology and nanomedicine in tumor therapy. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) presents promise as a cancer treatment method, but its efficacy faces challenges due to the inefficient Fenton catalytic reaction, where the transition metals' conversion from high to low valence states acts as the rate‐limiting step. Here, a strategy employing radioiodine is introduced to facilitate the valence conversion of transition metals for CDT enhancement. Iron‐based metal‐organic framework (MOF) nanoparticles (NPs) are synthesized labeled with radioiodine‐125 (125I), referred to as 125I‐MIL‐88B(Fe) NPs. These NPs possess a porous structure capable of concentrating and catalyzing H2O2 to generate highly toxic hydroxyl radicals (·OH). Furthermore, 125I can continuously produce hydrated electrons (eaq−) in aqueous environments, promoting the conversion of Fe3+/Fe2+ to boost ·OH production. In vitro and in vivo experiments validate the enhanced CDT effect on pancreatic cancer, driven by the reactive oxygen species (ROS)/mitogen‐activated protein kinase (MAPK)/p53 pathway‐mediated cell apoptosis. The radioiodine‐mediated electron‐supplying strategy not only amplifies the effectiveness of CDT but also unlocks new potential applications for radionuclides. [ABSTRACT FROM AUTHOR]

It is important but challenging to innovate inorganic sonosensitizers with controlled biodegradability and enhanced sonodynamic and chemodynamic activities to harness and remodel the immunosuppressive tumor microenvironment (TME) for awakening robust immune responses against metastatic cancers. Herein the rational design and defect engineering strategy of a pH‐responsive biodegradable sonozyme system in sulfide nanocages for augmented cancer immunotherapy is reported. A series of highly defective Co9S8‐x sonosensitizers with elevated sulfur‐vacancy (VS) levels are fabricated to systematically explore the VS‐dependent sonodynamic and chemodynamic properties by regulating the weight ratio of the sulfur to cobalt source. The bandgap is substantially reduced from 2.06 to 1.54 eV, and the atomic ratio of Co2+ to Co3+ is increased from 1.53 to 1.97. Therefore, the sonodynamic, chemodynamic, and antitumor immune responses of Co9S8‐x are dramatically augmented by defect engineering of a biodegradable sulfide sonozyme system. The slow degradation in the slightly acid TME substantially reduced the size for enhanced tumor targeting and infiltration, while exerting a slight influence on the sonodynamic performance. As a result, satisfactory therapeutic effects on the eradication of primary, distant, and metastatic tumors can be achieved. This work highlights the potential of defect engineering strategies in biodegradable sonosensitizers for enhanced immunotherapy in combating metastatic cancers. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) has great potential in cancer treatment, but its efficacy is limited due to non‐specificity, insufficient hydrogen peroxide (H2O2), and excessive glutathione (GSH) within the tumor microenvironment (TME). Here, an intelligent nanoplatform (Fe3O4@MnO2@NO@Au NPs, abbreviated as CD44FMNA) is reported for the treatment of breast cancer, which is constructed with Fe3O4 nanoparticles (NPs) as the core coated with manganese dioxide (MnO2) nanoshells encapsulating NO donors and gold nanoparticles (Au NPs) within the pores of MnO2, followed by the conjugation of targeting ligand anti‐CD44 mAb. The fabricated CD44FMNA initially remains inactive in normal cells, but after CD44 receptor ‐mediated MDA‐MB‐231 cell‐specific endocytosis, acidic TME can induce the decomposition of the MnO2 shell to release NO donors, thereby dually depleting the existing GSH in cells and enhancing the Fenton‐like reaction in a cascade manner. The generation of hydroxyl radicals (·OH) and the dual depletion of GSH can significantly weaken the GSH‐related antioxidant defense system (ADS) within MDA‐MB‐231 cells, accelerating apoptosis and cell death via the mitochondrial pathway. In addition, in vivo studies demonstrate that CD44FMNA can effectively inhibit tumor growth with good biosafety. Therefore, this nanoplatform may provide an effective therapy for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

With breast cancer emerging as a pressing global health challenge, characterized by escalating incidence rates and geographical disparities, there is a critical need for innovative therapeutic strategies. This comprehensive research navigates the landscape of nanomedicine, specifically focusing on the potential of magnetic nanoparticles (MNPs), with magnetite (Fe3O4) taking center stage. MNPs, encapsulated in biocompatible polymers like silica known as magnetic silica nanoparticles (MSN), are augmented with phosphotungstate (PTA) for enhanced chemodynamic therapy (CDT). PTA is recognized for its dual role as a natural chelator and electron shuttle, expediting electron transfer from ferric (Fe3+) to ferrous (Fe2+) ions within nanoparticles. Additionally, protein-based charge-reversal nanocarriers like silk sericin and gluten are introduced to encapsulate (MSN-PTA) nanoparticles, offering a dynamic facet to drug delivery systems for potential revolutionization of breast cancer therapy. This study successfully formulates and characterizes protein-coated nanocapsules, specifically MSN-PTA-SER, and MSN-PTA-GLU, with optimal physicochemical attributes for drug delivery applications. The careful optimization of sericin and gluten concentrations results in finely tuned nanoparticles, showcasing uniform size, enhanced negative zeta potential, and remarkable stability. Various analyses, from Dynamic Light Scattering (DLS) and scanning electron microscopy (SEM) to transmission electron microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR), X-Ray diffraction analysis (XRD), and Thermogravimetric analysis (TGA), provide insights into structural integrity and surface modifications. Vibrating Sample Magnetometer (VSM) analysis underscores superparamagnetic behavior, positioning these nanocapsules as promising candidates for targeted drug delivery. In vitro evaluations demonstrate dose-dependent inhibition of cell viability in MCF-7 and Zr-75–1 breast cancer cells, emphasizing the therapeutic potential of MSN-PTA-SER and MSN-PTA-GLU. The interplay of surface charge and pH-dependent cellular uptake highlights the robust stability and versatility of these nanocarriers in tumor microenvironment, paving the way for advancements in targeted drug delivery and personalized nanomedicine. This comparative analysis explores the suitability of silk sericin and gluten, unraveling a promising avenue for the development of advanced, targeted, and efficient breast cancer treatments. [ABSTRACT FROM AUTHOR]

An intelligent nanodrug delivery system (Cu/ZIF-8@GOx-DOX@HA, hereafter CZGDH) consisting of Cu-doped zeolite imidazolate framework-8 (Cu/ZIF-8, hereafter CZ), glucose oxidase (GOx), doxorubicin (DOX), and hyaluronic acid (HA) was established for targeted drug delivery and synergistic therapy of tumors. The CZGDH specifically entered tumor cells through the targeting effect of HA and exhibited acidity-triggered biodegradation for subsequent release of GOx, DOX, and Cu2+ in the tumor microenvironment (TME). The GOx oxidized the glucose (Glu) in tumor cells to produce H2O2 and gluconic acid for starvation therapy (ST). The DOX entered the intratumoral cell nucleus for chemotherapy (CT). The released Cu2+ consumed the overexpressed glutathione (GSH) in tumor cells to produce Cu+. The generated Cu+ and H2O2 triggered the Fenton-like reaction to generate toxic hydroxyl radicals (·OH), which disrupted the redox balance of tumor cells and effectively killed tumor cells for chemodynamic therapy (CDT). Therefore, synergistic multimodal tumor treatment via TME-activated cascade reaction was achieved. The nanodrug delivery system has a high drug loading rate (48.3 wt%), and the three-mode synergistic therapy has a strong killing effect on tumor cells (67.45%). [ABSTRACT FROM AUTHOR]