Camouflaged Nanozymes with Oxidation-Promoting Activities Triggering Ferroptosis for Radio-Immunotherapy

Abstract

Radioresistance presents a substantial obstacle to achieving optimal therapeutic outcomes for breast cancer treatment. In this study, we develop a cancer cell membrane (CM) - coated nanozyme system (MPPC@CM), specifically designed for radioimmunotherapy to address this issue. This innovative system involves the in situ reduction of platinum and palladium on mesoporous silica nanospheres, followed by functionalization with cinnamaldehyde via surface grafting. The CM coating endows the nanozyme with enhanced tumor-specific targeting capability due to its homing properties. Upon uptake by tumor cells, MPPC@CM catalytically generates O2 from H2O2, mitigating the hypoxic tumor microenvironment and reducing radioresistance. The intracellular glutathione depletion mediated by Michael addition reactions concurrently disrupts endogenous antioxidant defenses against reactive oxygen species (ROS). This redox imbalance is synergistically amplified through nanozyme-mediated catalytic activities including both peroxidase-like and oxidase-like functions. The resultant massive ROS accumulation establishes a self-reinforcing oxidative cascade that ultimately induces functional inactivation of glutathione peroxidase 4. The immunosuppressive environment is remodeled by this disturbance in redox balance, which accelerates ferroptosis and increases CD8+ T-cell infiltration and dendritic cell maturation. Overall, this cell membrane-camouflaged nanozyme holds significant potential to enhance the efficacy of radioimmunotherapy.