Engineering MnPt Bimetallic Nanozymes for Cascade Enzymatic Therapy and Enhanced Radio‐Immunotherapy

ABSTRACT The immunosuppressive tumor microenvironment (TME) promotes resistance to radiation therapy, substantially limiting the efficacy of radioimmunotherapy. Here, we report a hyaluronic acid (HA)‐coated manganese–platinum (MnPt) bimetallic nanozyme (HD@MnO 2 ) that integrates enzymatic cascade initiation with cGAS–STING pathway activation to facilitate radioimmunotherapy for breast cancer treatment. The HD@MnO 2 features a cationic MnO 2 core sequentially modified with HA and cisplatin, enabling CD44‐targeted delivery and improved biocompatibility. Leveraging the reversible valence cycling of Mn and Pt in the TME, HD@MnO 2 offers multienzyme‐like activity, which collectively enhances H 2 O 2 utilization, depletes glutathione, and promotes O 2 generation. These cascade reactions combined with radiotherapy effectively trigger bursts of ROS production, disrupt redox homeostasis, and induce immunogenic cell death. Concurrently, released Mn 2 + activates the cGAS–STING pathway, thereby boosting innate immunity. The combination of these effects promotes dendritic cell maturation and increases CD8 + T cell infiltration, thereby establishing a radiotherapy‐immune mutual amplification loop. Both in vitro and in vivo experiments demonstrated that HD@MnO 2 markedly eliminates primary tumors and suppresses metastatic tumors by overcoming radioresistance and eliciting potent systemic antitumor immunity. Overall, this approach offers a promising strategy for addressing the conventional limitations of radioimmunotherapy.