BoostingPeroxidase-Mimetic Activity of FeMn-NC_e Dual-Atom RadiosensitizingNanozymes for Augmented RadiodynamicImmunotherapy

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-NC_e 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-NC_e 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-NC_e 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.