X-ray-Activated Asymmetric Cobalt Single-Atom Nanozyme Potentiates Catalytic Immunotherapy via Enhanced Peroxidase-Like Activity.

Single-atom nanozymes (SAzymes) have emerged as promising platforms for catalytic therapy owing to their atomic precision and tunable electronic structures. Here, we report an asymmetrically coordinated cobalt SAzyme featuring Co-N3C active sites anchored within a hafnium-based metal-organic framework (Hf-MOF). The engineered HfCoNC nanozyme exhibits significantly enhanced peroxidase-like activity and enables efficient X-ray-activated catalytic immunotherapy. The asymmetric Co-N3C coordination optimizes substrate adsorption and lowers the reaction energy barrier, thereby accelerating the catalytic reaction. In the tumor microenvironment, HfCoNC efficiently converts endogenous H2O2 into highly cytotoxic hydroxyl radicals (•OH), while low-dose X-ray irradiation further amplifies reactive oxygen species (ROS) production. The resulting oxidative stress induces extensive DNA damage and activates the cGAS-STING signaling pathway. Moreover, the release of Co2+ ions, together with the co-delivered STING agonist, further potentiates systemic antitumor immunity, effectively suppressing tumor growth and metastasis. This work provides a promising strategy for developing SAzyme-based platforms for synergistic catalytic radioimmunotherapy.