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

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.