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

Abstract Chemodynamic therapy (CDT) has garnered significant attention in the field of tumor therapy due to its ability to convert overexpressed hydrogen peroxide (H 2 O 2 ) 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 H 2 O 2 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 H 2 O 2 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 H 2 O 2 and gluconic acid in situ. Subsequently, the reduced pH triggers the release of Fe 3+ and Cu 2+ from CuFeMOF@GOx@Mem, which is immediately turned into Fe 2+ and Cu + by GSH, activating the Fe 2+ ‐mediated Fenton reaction. More importantly, Cu + can also act as an accelerator of Fe 3+ /Fe 2+ conversion, meanwhile, the generated Cu 2+ can be further reduced to Cu + by GSH. Consequently, sustained accumulation of H 2 O 2 and Fe 2+ as well as sustained elimination of GSH are achieved simultaneously, providing a unique approach for improving the anti‐tumor ability of CDT.