Zr‐Based Metal–Organic Framework Dual‐Sensitized by Carbon Dot Sonosensitizers and MnO _2−x Nanozymes for cGAS‐STING Activation Enhanced Sonocatalytic‐Immunotherapy

Abstract Reactive oxygen species (ROS)‐mediated immunogenic cell death (ICD) is believed to stimulate DC maturation and initiate the infiltration of cytotoxic T lymphocytes. Nevertheless, the effectiveness of sonodynamic and nanocatalytic therapy (SDT/NCT) is hindered by the restricted ROS generation and immunosuppressive tumor microenvironments (TME). To address these issues, the first time the dual‐sensitization of Zr‐based metal–organic framework (Zr‐MOF) is reported through the loading of carbon dot (CD) sonosensitizers and the depositing of oxygen‐vacancy‐doped MnO 2−x nanozymes. The fabricated Z‐scheme CD/Zr‐MOF/MnO 2−x heterojunctions exhibit cascade amplification of ROS production owing to the enhanced SDT efficiency, hypoxia alleviation, POD‐like activity, and GSH consumption. The immunosuppressive TME is reversed by the cascade amplification of ROS generation, thereby inducing potent ICD and promoting DC maturation. The maturation of DCs is further amplified by the activation of the cGAS‐STING pathway through the tumor‐specific release of Mn ions. CD/Zr‐MOF/MnO 2−x ‐mediated combination therapy of SDT, NCT, and cGAS‐STING activation exhibits significant antitumor effects, resulting in the eradication of primary tumors and the inhibition of distant tumor growth. This study provides promising insights into the exploration of an Mn‐based nanoplatform that integrates sonosensitizer, nanozyme, and STING nanoagonist functions for cGAS‐STING activation enhanced sonocatalytic‐immunotherapy to produce long‐lasting and powerful immune responses.