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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]

BACKGROUND: The low catalytic activity and lack of targeting of commonly used metal ions have severely limited the clinical application of chemodynamic therapy in tumor treatment. On the other hand, although the composite nanoplatforms are endowed with tumor-targeting functions by surface functionalization, the lack of tumor microenvironment acidity also severely weakens the efficacy of chemodynamic therapy. OBJECTIVE: To prepare novel composite nanoplatforms and assess their feasibility to enhance the effects of chemodynamic therapy at the cellular level. METHODS: SLC-0111-loaded zeolite imidazole framework-8 doped with divalent iron ions (Fe2+) and divalent cobalt ions (Co2+) (Fe-Co/ZIF-8@SLC-0111) was synthesized by ion-exchange reaction and self-assembly, and loaded with hyaluronic acid (HA) by electrostatic adsorption, followed by obtaining the target nanoparticles Fe-Co/ZIF-8@SLC-0111-HA (abbreviated as FC-S). Meanwhile, nanoparticles Fe-Co/ZIF-8-HA (abbreviated as FC) without SLC-0111 were synthesized by the same method. The nanocomposite platform was tested for particle size, zeta potential, surface morphology, in vitro reactive oxygen species generation, and ability to consume glutathione. Human osteosarcoma cell MG-63 and mouse fibroblast cell L929 were used as experimental subjects. The cytotoxicity of FC-S was detected by CCK-8 assay. Human osteosarcoma cell MG-63 was used as the experimental object to detect the cell internalization of FC-S. In addition to H2O2, the effects of FC-S and FC on intracellular pH, carbonic anhydrase 9 protein expression, cell viability and apoptosis, intracellular reactive oxygen species and glutathione content, and mitochondrial membrane potential were investigated. RESULTS AND CONCLUSION: (1) The FC-S composite nanoplatform was successfully prepared with a well-defined rhombic dodecahedral structure, uniform size and good dispersion. Its particle size was about 323 nm; zeta potential was about -11.1 mV, and the nanoplatform had a certain reactive oxygen species generation capacity in vitro. (2) FC-S nanoplatforms accumulated intracellularly in a time-dependent manner and could successfully escape from lysosomes. When the mass concentration of FC-S was ≤ 20 µg/mL, there was no obvious cytotoxicity to MG-63 cells and L929 cells, and 20 µg/mL FC-S was selected to act on MG-63 cells in subsequent experiments. (3) Compared with FC group, the protein expression of carbonic anhydrase 9 in MG-63 cells in FC-S group was decreased (P < 0.01); the intracellular acidic environment was enhanced; the content of reactive oxygen species was increased (P < 0.001); the mitochondrial damage was aggravated; the number of dead cells was increased, and the apoptosis rate was increased (P < 0.001). (4) The results indicate that FC-S, as a novel composite nanoplatform, can effectively improve the weakly acidic microenvironment in tumor cells and enhance the level of intracellular reactive oxygen species production, thus enhancing the efficacy of chemodynamic therapy. [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 The development of efficient therapeutic strategies to promote ferroptotic cell death offers significant potential for hepatocellular carcinoma (HCC) treatment. Herein, this study presents an HCC‐targeted nanoplatform that integrates bimetallic FeMoO4 nanoparticles with CO‐releasing molecules, and further camouflaged with SP94 peptide‐modified macrophage membrane for enhanced ferroptosis‐driven multi‐modal therapy of HCC. Leveraging the multi‐enzyme activities of the multivalent metallic elements, the nanoplatform not only decomposes H2O2 to generate oxygen and alleviate tumor hypoxia but also depletes glutathione to inactivate glutathione peroxides 4, which amplify sonodynamic therapy and ferroptotic tumor death under ultrasound (US) irradiation. Meanwhile, the nanoplatform catalyzes the Fenton reaction to produce hydroxyl radicals for chemodynamic therapy. Elevated intracellular reactive oxygen species trigger the cascade release of CO, leading to lethal lipid peroxidation and further enhancing ferroptosis‐mediated tumor therapy. This nanoplatform demonstrates robust anti‐tumor efficacy under US irradiation with favorable biosafety in both subcutaneous and orthotopic HCC models, representing a promising therapeutic approach for HCC. Additionally, the findings offer new insights into tumor microenvironment modulation to optimize US‐triggered multi‐modal cancer therapy.

Abstract Transarterial chemoembolization (TACE) utilizing a water‐in‐oil lipiodol emulsion is a preferable therapeutic strategy for advanced liver cancer in clinical practice. However, the low stability of the lipiodol emulsion and poor efficacy of chemotherapeutic drug seriously undermine the efficiency of TACE. Herein, a novel lobaplatin‐loaded lipiodol emulsion (denoted as ICN‐LPE) is developed by constructing a lipiodol Pickering emulsion (LPE) stabilized with iron‐doped carbon nanozymes (ICN) to mitigate the issue of lipiodol‐water separation. This novel emulsion not only solves the instability of conventional lipiodol emulsions, but also facilitates the sustained release of lobaplatin. More importantly, upon entry into tumor cells, ICN catalyze the generation of reactive oxygen species via the Fenton‐like reaction while simultaneously consuming intracellular glutathione, thereby inducing tumor cell death via chemodynamic therapy. By integrating chemotherapy and chemodynamic therapy, ICN‐LPE demonstrates a synergistic antitumor effect and effectively inhibits tumor growth in a rabbit liver tumor model. Therefore, our ICN‐LPE shows an appealing clinical application prospect for TACE.

Abstract Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis. Extra intracellular Cu induces cuproptosis and chemodynamic therapy (CDT), which further cascades immunogenic cell death (ICD) and activates antitumor immune responses. However, the tumor immunosuppressive microenvironment (TIM) attenuates the efficiency of the immune response. Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu2+ and NLG919 (an IDO1 inhibitor) are integrated via a self‐assembly process and subsequently coated with 4T1 cell membrane. ECNM can overcome the typical drawbacks of ES, ameliorating the stability and half‐life of ES by membrane‐coating and enhancing its tumor accumulation and internalization via homotypic targeting. It is worth mentioning that, the addition of NLG919 is also beneficial to the system circulation stability of ES and reduces the non‐specific ES release. After internalization, ECNM dissociates via the glutathione‐responsive process and exhibits comprehensive antitumor capabilities, including cuproptosis, CDT and TIM reversing, thereby eliciting ICD and optimizing the antitumor immune response. Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer 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.

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.

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

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.

Jing Kong,1,&ast; Jiabin Lai,2– 4,&ast; Min Wang,5,&ast; 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&ast;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

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.

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

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]

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]

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]

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 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]

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]

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]

Prodrug‐based self‐assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH‐responsive ARS‐4‐hydroxybenzoyl hydrazide (HBZ)‐5‐amino levulinic acid (ALA) nanoparticles (AHA NPs) with self‐supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS‐HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS‐HBZ for excellent anti‐tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) has received increasing attention in recent years due to its effectiveness and specificity. However, the limited endogenous hydrogen peroxide (H2O2) concentration and resistance to reactive oxygen species in cancer cells hinder the further application of CDT. Here, an H2O2 self‐supplied nanosystem FCaO2@ZIF‐67‐2‐DG‐FA (FZDF) is synthesized to achieve efficient CDT improvement by Ca2+ overload and starvation therapy. Under folic acid‐mediated tumor targeting and endocytosis, the ZIF‐67 layer of FZDF is cleaved in the mildly acidic environment, releasing Co2+ and 2‐deoxy‐D‐glucose (2‐DG). The decomposition of exposed FCaO2 generates sufficient H2O2, which further produces abundant •OH via the Fenton‐like reaction of Co2+. Simultaneously, Ca2+ overload‐triggered mitochondrial dysfunction couples with glycolysis inhibition via 2‐DG‐induced starvation, which disrupts intracellular adenosine triphosphate (ATP) synthesis and amplifies the efficacy of CDT. Silicon nanoparticles released from FCaO2 are applied as in vitro fluorescent probes to image tumor cells overexpressing folate receptors. The results have presented that FZDF can actively accumulate in tumor cells, causing the mitochondrial membrane potential abnormality and a decrease in intracellular ATP content, thereby enhancing the self‐supplied CDT with less effect on normal cells and tissues. This work provides a novel strategy for constructing effective CDT nanosystems by hindering intracellular energy supply. [ABSTRACT FROM AUTHOR]

[Display omitted] Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO 3 @MnO 2 -NH 2 @GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO 3 nanoparticles wrapped in a MnO 2 shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO 2 decomposes H 2 O 2 in cancer cells into O 2 , which enhances the efficiency of GOx-mediated starvation therapy. CaCO 3 can be decomposed in the acidic cancer cell environment, causing Ca2+ overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the H 2 O 2 and gluconic acid produced during glucose consumption by GOx are utilized by MnO 2 with catalase-like activity to enhance O 2 production and Mn2+ release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO 3 decomposition, promoting the Ca2+ release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca2+ overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) alone cannot achieve sufficient therapeutic effects due to the excessive glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Developing a novel strategy to improve efficiency is urgently needed. Herein, we prepared a copper silicate nanoplatform (CSNP) derived from colloidal silica. The Cu(II) in CSNP can be reduced to Cu(I), which cascades to induce a subsequent CDT process. Additionally, benefiting from GSH depletion and oxygen (O2) generation under 660 nm laser irradiation, CSNP exhibits both Fenton-like and hypoxia-alleviating activities, contributing to the effective generation of superoxide anion radical (•O2−) and hydroxyl radical (•OH) in the TME. Furthermore, given the suitable band-gap characteristic and excellent photochemical properties, CSNP can also serve as an efficient type-I photosensitizer for photodynamic therapy (PDT). The synergistic CDT/PDT activity of CSNP presents an efficient antitumor effect and biosecurity in both in vitro and in vivo experiments. The development of an all-in-one nanoplatform that integrates Fenton-like and photosensing properties could improve ROS production within tumors. This study highlights the potential of silicate nanomaterials in cancer treatment. [ABSTRACT FROM AUTHOR]

The combination of ferroptosis, cuproptosis, and chemodynamic therapy (CDT) would be a potential strategy for tumor diagnosis and enhanced treatment. However, the therapeutic effect was severely limited by the lack of specific delivery of catalytic ions and the low Fenton reaction efficiency in tumor microenvironment (TME) with excess glutathione, limited acidity and insufficient endogenous hydrogen peroxide. In this work, p-carboxybenzenesulfonamide (BS), a carbonic anhydrase IX (CA IX) inhibitor, was modified on the surface of generation-5 poly(amidoamine) dendrimer to load copper peroxide nanoparticles, which were complexed with iron (Fe)-tannic acid (TF) networks for targeted magnetic resonance (MR) imaging and enhanced ferroptosis/cuproptosis/CDT by regulating TME. The formed CuO 2 @G5-BS/TF nanocomplexes with an average size of 39.4 nm could be specifically accumulated at tumor site and effectively internalized by metastatic 4T1 cells via the specific interaction between BS and CA IX over-expressed on tumor cells. Meanwhile, the inhibition of CA IX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H 2 O 2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity in TME. Moreover, the reduction of Fe3+/Cu2+ by intracellular glutathione (GSH) could further amplify ROS generation and enhance CDT efficacy, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy. In vivo experimental results demonstrated that CuO 2 @G5-BS/TF could provide better tumor MR imaging, effectively inhibit the growth and metastasis of 4T1 breast tumors, and be metabolized without significant systemic toxicity. Thus, CuO 2 @G5-BS/TF nanocomplexes provided a new approach for targeted MR imaging and enhanced ferroptosis/cuproptosis/CDT of triple-negative breast cancer. Taking the advantage of dendrimer and metal-phenolic system, stable CuO 2 @G5-BS/TF nanocomplexes with an average size of 39.4 nm were synthesized to efficiently load Fe3+ and CuO 2 nanoparticles for TNBC treatment and MR imaging. CuO 2 @G5-BS/TF nanocomplexes could target tumor cells overexpressing CAIX via the specific binding with BS, and the inhibition of CAIX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H 2 O 2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity. The reduction of Fe3+/Cu2+ by intracellular GSH could further amplify ·OH generation, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy by enhanced ferroptosis/cuproptosis/CDT via tumor microenvironment regulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite multifunctional theranostics hold vast potential in deep tissue bioimaging and tumor therapy, activatable nanomedicine with integration of precise diagnosis and effective treatment is usually achieved at the cost of complicated synthesis chemistries. Here, a facile way to design bioresponsive Ag2S‐Ag Janus probes coated by polyethylene glycol (PEG) (denoted as AAP) is showed, active in the second near‐infrared window (NIR‐II, 1000–1700 nm). In tumor microenvironment, Ag part can yield hydroxyl radicals (·OH) by consuming H2O2 for high‐efficiency chemodynamic therapy (CDT), while Ag2S part has impressive photothermal therapy (PTT). The synergistic benefits from Ag and Ag2S parts further boosted CDT effect of AAP Janus probes with high photothermal conversion efficiency up to 56.8%. Moreover, multiple lines of evidence supported that extremely faint fluorescence of AAP Janus probes can be significantly activated by overexpressed levels of H2O2, showing bright NIR‐II emission at ≈1270 nm with over 5.6 × 103‐fold increase in signal intensity. AAP Janus probes are easily activatable for NIR‐II imaging for tumor‐specific identification, and effectively ablate tumor tissues with tumor inhibition rate of 96.2%. This study expects that AAP Janus probe will open up a new route to achieve precise tumor diagnosis and treatment in the NIR‐II window. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood–brain barrier (BBB) to reach the GBM is another endless marathon. In this review, the physiology of the BBB has been elaborated to understand the mechanism of crossing these potential barriers to treat GBM. Moreover, the designing of Fenton-based nanomaterials has been discussed for the production of reactive oxygen species in the tumor area to eradicate the cancer cells. For effective tumor targeting, biological nanomaterials that can cross the BBB via neurovascular transport channels have also been explored. To overcome the neurotoxicity caused by inorganic nanomaterials, the use of smart nanoagents having both enhanced biocompatibility and effective tumor targeting ability to enhance the efficiency of CDT are systematically summarized. Finally, the advancements in intelligent Fenton-based nanosystems for a multimodal therapeutic approach in addition to CDT are demonstrated. Hopefully, this systematic review will provide a better understanding of Fenton-based CDT and insight into GBM treatment. [ABSTRACT FROM AUTHOR]

Despite significant breakthroughs in immunotherapy, the limitations of inadequate immune stimulation and stubborn immune resistance continue to present opportunities and challenges. Therefore, a two‐pronged approach, encompassing the activation of immunogenic cell death (ICD) and blocking the indoleamine 2,3‐dioxygenase (IDO)‐mediated pathway, is devised to elicit systemic anti‐tumor immunity and alleviate immunosuppression. Herein, a tumor microenvironment (TME)‐specific driven nanoagent is composed of a tetrasulfide bond‐bridged mesoporous silica layer (MON) coated up‐conversion nanoparticles as a nano‐carrier, combines Fe2+, curcumin, and indoximod for operating chemodynamic therapy/chemotherapy/immunotherapy. The consumption of glutathione (GSH) caused by MON degradation, the Fenton reaction of Fe2+, and curcumin triggering mitochondrial damage collectively exacerbate the oxidative stress, leading to a violent immunoreaction and reversal of the immunosuppressive TME through a combination of IDO‐inhibitors. Meanwhile, upconversion luminescence (UCL) imaging serves as a significant guiding tool for drug delivery and the treatment of nanoagents. In vivo and in vitro experiment results demonstrate that the nanosystem not only effectively inhibits the growth of primary tumors but also induces immune priming and memory effects to reject re‐challenged tumors. The strategy as a complementary approach displays great potential for future immunotherapy along with other multimodal treatment modes. [ABSTRACT FROM AUTHOR]

Bacterial infections pose a global concern due to high fatality rates, particularly with the rise of drug-resistant bacteria and biofilm formation. There is an urgent need for innovative strategies to combat this issue. A study on chemodynamic therapy (CDT) using nanozymes in conjunction with photothermal therapy (PTT) has displayed potential in addressing drug-resistant bacterial infections. However, the effectiveness of this combined approach is limited by inadequate light absorption. This work suggests the NiOx nanoparticles enriched with oxygen vacancies enhance CDT and PTT to overcome this challenge. The presence of oxygen vacancies in NiOx can reduce the energy gap between its valence band and conduction band, facilitating oxygen adsorption. NiOx has exhibited notable antibacterial properties and complete eradication of biofilms in both laboratory and animal trials. In animal abscess models, NiOx demonstrated antibacterial and anti-inflammatory effects in the initial stages, while also promoting wound healing and tissue regeneration by influencing immune factors and encouraging collagen deposition and neovascularization. With positive biosafety and biocompatibility profiles, the oxygen vacancy-enhanced CDT and PTT therapy proposed in this article hold promise for effective sterilization, deep biofilm removal, and treatment of infections caused by drug-resistant bacteria. This study constructs oxygen vacancies NiOx nanoparticles (NiOx NPs) to improve the efficacy of photothermal therapy and chemodynamic therapy. The presence of oxygen vacancies in NiOx NPs helps bridge the energy gap between its valence band and conduction band, facilitating oxygen adsorption and improving catalytic efficiency. In both in vivo and in vitro antibacterial experiments, NiOx NPs demonstrate effective antibacterial and anti-inflammatory properties. Furthermore, it aids in wound healing and tissue regeneration by modulating immune factors, collagen deposition, and angiogenesis. This approach presents a promising collaborative strategy for utilizing nickel-based defective nanomaterials in combating deep drug-resistant bacterial infections. [Display omitted] [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT), an inventive approach to cancer treatment, exploits innate chemical processes to trigger cell death through the generation of reactive oxygen species (ROS). While offering advantages over conventional treatments, the optimization of CDT efficacy presents challenges stemming from suboptimal catalytic efficiency and the counteractive ROS scavenging effect of intracellular glutathione (GSH). In this study, we aim to address this dual challenge by delving into the role of copper valence states in CDT. Leveraging the unique attributes of copper-based nanoparticles, especially zero-valent copper nanoparticles (CuPd NPs), we aim to enhance the therapeutic potential of CDT. Our experiments reveal that zero-valent CuPd NPs outperform divalent copper nanoparticles (Ox-CuPd NPs) by displaying superior catalytic performance and sustaining ROS generation through a dual approach integrating peroxidase-like (POD-like) activity and Cu+ release. Notably, zero-valent NPs exhibit enhanced GSH depletion compared to their divalent counterparts, thereby intensifying CDT and inducing ferroptosis, ultimately resulting in high-efficiency tumor growth inhibition. These findings reveal the impact of valences on CDT, providing novel insights for the optimization and design of CDT agents. [ABSTRACT FROM AUTHOR]

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Abstract Chemodynamic therapy (CDT) has shown promising antitumor effects in various malignant tumors. However, its application for glioblastoma (GBM) is significantly hindered by the challenge of delivering CDT agents across the blood‐brain barrier (BBB) and achieving efficient tumor targeting. To overcome these obstacles, this study presents a novel DNA nanomachine (Cu@tFNAs‐G‐A NM) by loading copper ions (Cu2+) onto tetrahedral framework nucleic acids (tFNAs) functionalized with dual DNA aptamers. The dual DNA aptamers (GS24 for BBB penetration and AS1411 for tumor targeting) empowered Cu@tFNAs‐G‐A NM with the ability to effectively penetrate the BBB and selectively accumulate in tumor cells. Upon internalization, the loaded Cu2+ reacted with tumor‐overexpressed reductive glutathione (GSH) and hydrogen peroxide (H2O2), generating hydroxyl radicals (·OH) and inducing tumor cell death. Additionally, Cu@tFNAs‐G‐A NM was found to be rapidly cleared from the brain and normal tissues within 24 h, minimizing potential systemic toxic side effects. These findings demonstrate the promising potential of Cu@tFNAs‐G‐A NM for effective CDT against GBM and open up new avenues for the development of targeted therapies for GBM.

Chen Wang,1,&ast; Hongmei Zhou,1,&ast; Mekhrdod S Kurboniyon,2 Yanping Tang,1 Zhengmin Cai,1 Shufang Ning,1 Litu Zhang,1 Xinqiang Liang1 1Department of Research & Guangxi Cancer Molecular Medicine Engineering Research Center & Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2National Academy of Sciences of Tajikistan, Dushanbe, Tajikistan&ast;These authors contributed equally to this workCorrespondence: Litu Zhang; Xinqiang Liang, Department of Research and Guangxi Cancer Molecular Medicine Engineering Research Center and Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China, Email zhanglitu@gmail.com; xx03716@163.comBackground: Chemodynamic therapy (CDT) is a new treatment approach that is triggered by endogenous stimuli in specific intracellular conditions for generating hydroxyl radicals. However, the efficiency of CDT is severely limited by Fenton reaction agents and harsh reaction conditions.Methods: Bimetallic PtMn nanocubes were rationally designed and simply synthesized through a one-step high-temperature pyrolysis process by controlling both the nucleation process and the subsequent crystal growth stage. The polyethylene glycol was modified to enhance biocompatibility.Results: Benefiting from the alloying of Pt nanocubes with Mn doping, the structure of the electron cloud has changed, resulting in different degrees of the shift in electron binding energy, resulting in the increasing of Fenton reaction activity. The PtMn nanocubes could catalyze endogenous hydrogen peroxide to toxic hydroxyl radicals in mild acid. Meanwhile, the intrinsic glutathione (GSH) depletion activity of PtMn nanocubes consumed GSH with the assistance of Mn3+/Mn2+. Upon 808 nm laser irradiation, mild temperature due to the surface plasmon resonance effect of Pt metal can also enhance the Fenton reaction.Conclusion: PtMn nanocubes can not only destroy the antioxidant system via efficient reactive oxygen species generation and continuous GSH consumption but also propose the photothermal effect of noble metal for enhanced Fenton reaction activity.Keywords: noble metal, Mn-doping, Fenton reaction, photothermal effect, chemodynamic therapy

Abstract Osteosarcoma (OS) is an aggressive bone tumor with strong invasiveness, rapid metastasis, and dreadful mortality. Chemotherapy is a commonly used approach for OS treatment but is limited by the development of drug resistance and long-term adverse effects. To date, OS still lacks the curative treatment. Herein, we fabricated pyrite-based nanoparticles (FeS2@CP NPs) as synergetic therapeutic platform by integrating photothermal therapy (PTT) and chemo-dynamic therapy (CDT) into one system. The synthetic FeS2@CP NPs showed superior Fenton reaction catalytic activity. FeS2@CP NPs-based CDT efficaciously eradicated the tumor cells by initiating dual-effect of killing of apoptosis and ferroptosis. Furthermore, the generated heat from FeS2@CP under near-infrared region II (NIR-II) laser irradiation could not only inhibit tumor’s growth, but also promote tumor cell apoptosis and ferroptosis by accelerating •OH production and GSH depletion. Finally, the photothermal/NIR II-enhanced CDT synergistic therapy showed excellent osteosarcoma treatment effects both in vitro and in vivo with negligible side effects. Overall, this work provided a high-performance and multifunctional Fenton catalyst for osteosarcoma synergistic therapy, which provided a pathway for the clinical application of PTT augmented CDT.

Abstract The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.