H2O2 Self-Supplying and GSH-Depleting Nanocatalyst for Copper Metabolism-Based Synergistic Chemodynamic Therapy and Chemotherapy

Abstract

Chemodynamic therapy (CDT) that involves the use of Fenton catalysts to convert endogenous hydrogen peroxide (H₂O₂) to hydroxyl radicals (·OH) constitutes a promising strategy for cancer therapy; however, insufficient endogenous H₂O₂ 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@CuO₂) and can self-supply exogenous H₂O₂ and respond to specific tumor microenvironments (TME). Following endocytosis into tumor cells, DOX@MSN@CuO₂ initially decomposes into Cu²⁺ and exogenous H₂O₂ in the weakly acidic TME. Subsequently, Cu²⁺ reacts with high GSH concentrations, thereby inducing GSH depletion and reducing Cu²⁺ to Cu⁺ Next, the generated Cu⁺ undergoes Fenton-like reactions with exogenous H₂O₂ 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 H₂O₂ and GSH overexpression. Integrating H₂O₂ self-supply and GSH deletion enhances CDT, and DOX-induced chemotherapy endows DOX@MSN@CuO₂ with effective tumor growth-inhibiting properties alongside minimal side effects in vivo.

Keywords: chemodynamic therapy; copper metabolism; exogenous hydrogen peroxide; synergistic therapy; tumor microenvironment.