HO Self-Supplying and GSH-Depleting Nanocatalyst for Copper Metabolism-Based Synergistic Chemodynamic Therapy and Chemotherapy.

Chemodynamic therapy (CDT) that involves the use of Fenton catalysts to convert endogenous hydrogen peroxide (HO) to hydroxyl radicals (·OH) constitutes a promising strategy for cancer therapy; however, insufficient endogenous HO and glutathione (GSH) overexpression render its efficiency unsatisfactory. Herein, we present an intelligent nanocatalyst that comprises copper peroxide nanodots and DOX-loaded mesoporous silica nanoparticles (MSNs) (DOX@MSN@CuO) and can self-supply exogenous HO and respond to specific tumor microenvironments (TME). Following endocytosis into tumor cells, DOX@MSN@CuO initially decomposes into Cu and exogenous HO in the weakly acidic TME. Subsequently, Cu reacts with high GSH concentrations, thereby inducing GSH depletion and reducing Cu to Cu Next, the generated Cu undergoes Fenton-like reactions with exogenous HO to accelerate toxic ·OH production, which exhibits a rapid reaction rate and is responsible for tumor cell apoptosis, thereby enhancing CDT. Furthermore, the successful delivery of DOX from the MSNs achieves chemotherapy and CDT integration. Thus, this excellent strategy can resolve the problem of insufficient CDT efficacy due to limited HO and GSH overexpression. Integrating HO self-supply and GSH deletion enhances CDT, and DOX-induced chemotherapy endows DOX@MSN@CuO with effective tumor growth-inhibiting properties alongside minimal side effects in vivo.