Peroxidase-like Active Nanomedicine with Dual Glutathione Depletion Property to Restore Oxaliplatin Chemosensitivity and Promote Programmed Cell Death

The nanocatalytic activity of nanozymes provides a vision for tumor treatment. However, the glutathione (GSH)-related antioxidant defense system (ADS) formed on the basis of excessive GSH in the tumor microenvironment limits its catalytic activity. Here, dendritic mesoporous silica nanoparticles (DMSNs) were employed as nanocarrier; ultrasmall Fe3O4 nano-particles, Mn2+ ions, and glutaminase inhibitor Telaglenastat (CB-839) were subsequently integrated into large mesopores of DMSNs, forming DMSN/Fe3O4-Mn@CB-839 (DFMC) nanomedicine. This nanomedicine exhibits peroxidase mimicking activities under acidic conditions, which catalyzes the decomposition of hydrogen peroxide (H2O2) into hydroxyl radical (*OH). This also promotes the formation of lipid peroxides, which is required for ferroptosis. Furthermore, this nanomedicine can effectively deplete the existing GSH, thereby enhancing reactive oxygen species (ROS)-mediated tumor catalytic therapy. Moreover, the introduced CB-839 blocks the endogenous synthesis of GSH, further enhancing GSH depletion performance, which reduces the excretion of oxaliplatin (GSH-related resistance) from tumor cells, thereby restoring the chemical sensitivity of oxaliplatin. The dual GSH depletion property significantly weakens the GSH-related ADS and restores the chemical sensitivity of oxaliplatin, leading to the high DFMC-induced apoptosis and ferroptosis of tumor cells. Our developed nanomedicine based on integrated nanotechnology and clinical drug may aid the development of tumor treatment.