Boosting Peroxidase-Mimetic Activity of FeMn-NCe Dual-Atom Radiosensitizing Nanozymes for Augmented Radiodynamic Immunotherapy

Dual-atom nanozymes (DAzymes) have garnered considerable attention as catalysts for reactive oxygen species (ROS)-based therapies, effectively leveraging ROS generation within the tumor microenvironment (TME). Herein, we introduce the FeMn-NCe DAzymes, which are meticulously engineered for enhanced peroxidase (POD)-mimetic activity and potent radiosensitization to advance radioimmunotherapy. Density functional theory (DFT) calculations reveal that FeMn-NCe DAzymes lower the energy barrier and increase the substrate affinity, enabling highly efficient catalytic performance. Within the TME, these DAzymes efficiently convert overexpressed hydrogen peroxide (H2O2) into hydroxyl radicals (•OH), potentially activating the cGAS-STING immune pathway. This POD-mimetic catalysis is further accelerated under X-ray irradiation, significantly enhancing radiosensitization. Additionally, a uniform coating of ultrasmall gold nanoparticles on FeMn-NCe significantly enhances X-ray absorption within cancer cells. The incorporation of the STING agonist diABZI onto the DAzymes induces long-term antitumor immunity, reprograms the immunosuppressive TME, and effectively suppresses tumor growth and metastasis following a single low-dose X-ray treatment. This work highlights a valuable strategy for designing DAzymes to advance radiodynamic immunotherapy.