Fenton-like nanoparticles capable of H2O2 self-supply and glutathione consumption for chemodynamic and chemotherapy of cancer†

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 H₂O₂ and inefficient Fenton activity. Herein, a GSH-depleting and H₂O₂ self-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 via a 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 H₂O₂ to improve the efficiency of a Cu-based Fenton-like reaction. Resultantly, this nanosystem featuring Fenton-like activity, GSH consumption, H₂O₂ self-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.