Fenton-like nanoparticles capable of H2O2self-supply and glutathione consumption for chemodynamic and chemotherapy of cancerElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4bm00930d

Chemodynamic therapy (CDT) utilizing the Fenton reaction to convert hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (OH) has recently drawn extensive interest in tumor treatment. However, the therapeutic efficiency of CDT often suffers from high concentrations of glutathione (GSH), insufficient endogenous H2O2and inefficient Fenton activity. Herein, a GSH-depleting and H2O2self-providing nanosystem that can efficiently load copper ions and doxorubicin (DOX) (MSN-Cu2+-DOX) to induce enhanced CDT and chemotherapy is proposed. The results show that MSN-Cu2+-DOX could release Cu2+and DOX under acidic conditions. Particularly, both the released Cu2+and Cu2+in MSN-Cu2+-DOX are available for OH production viaa Fenton-like reaction for CDT. Meanwhile, Cu2+undergoes a reduction to Cu+by depleting overexpressed GSH, thereby enhancing CDT. Moreover, the released DOX could not only be used for chemotherapy, but also promote the generation of endogenous H2O2to improve the efficiency of a Cu-based Fenton-like reaction. Resultantly, this nanosystem featuring Fenton-like activity, GSH consumption, H2O2self-sufficiency and chemotherapy exhibits a great antitumor effect with a tumor inhibition ratio of 93.05%. Overall, this study provides a promising strategy to enhance CDT for effective tumor therapy.