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.