A pH/GSH Dual-Responsive Triple Synergistic Bimetallic Nanocatalyst for Enhanced Tumor Chemodynamic Therapy

Chemodynamic therapy (CDT) has garnered significant attention in the field of tumor therapy due to its ability to convert overexpressed hydrogen peroxide (H₂O₂) in tumors into highly toxic hydroxyl radicals (•OH) through metal ion-mediated catalysis. However, the effectiveness of CDT is hindered by low catalyst efficiency, insufficient intra-tumor H₂O₂ level, and excessive glutathione (GSH). In this study, a pH/GSH dual responsive bimetallic nanocatalytic system (CuFeMOF@GOx@Mem) is developed by modifying red blood cell membranes onto glucose oxidase (GOx)-loaded Fe-Cu bimetallic MOFs, enhancing the efficacy of CDT through a triple-enhanced way by H₂O₂ self-supply, catalysts self-cycling, and GSH self-elimination. Upon accumulation in tumor tissues facilitated by the red blood cell membrane, the GOx initiates a reaction with glucose to generate H₂O₂ and gluconic acid in situ. Subsequently, the reduced pH triggers the release of Fe³⁺ and Cu²⁺ from CuFeMOF@GOx@Mem, which is immediately turned into Fe²⁺ and Cu⁺ by GSH, activating the Fe²⁺-mediated Fenton reaction. More importantly, Cu⁺ can also act as an accelerator of Fe³⁺/Fe²⁺ conversion, meanwhile, the generated Cu²⁺ can be further reduced to Cu⁺ by GSH. Consequently, sustained accumulation of H₂O₂ and Fe²⁺ as well as sustained elimination of GSH are achieved simultaneously, providing a unique approach for improving the anti-tumor ability of CDT.