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Bacteria-Mediated Tumor-Targeting Delivery of Multienzyme-Mimicking Covalent Organic Frameworks Promoting Pyroptosis for Combinatorial Sono-Catalytic Immunotherapy

Yunyun Liu,Lihua Xiang,Yitong Li,Shen Zhang,Ying Zhang,Hui Shi,Hui Liu,Dou Du,Bangguo Zhou,Beibei Ye,Shaoyue Li,Haohao Yin,Huixiong Xu,Yifeng Zhang

Pyroptosis, an inflammatory cell death, has attracted great attention for potentiating a strong immune response against tumor cells. However, developing powerful pyroptosis inducers and then activating specific pyroptosis still remains challenging. Herein, a PEG-CuP-COF@∆St nanosystem is rationally designed, consisting of PEG-CuP-COF nanozyme pyroptosis inducers and tumor-targeting bacteria of the Salmonella Typhimurium strain VNP20009 (ΔSt), with an affinity for the tumor hypoxic microenvironment. The PEG-CuP-COF nanozymes possessed excellent sonodynamic performance and multienzyme-mimicking activities to generate reactive oxygen species (ROS) and then induce potent pyroptosis. The superoxide dismutase- and peroxidase-mimicking activities of PEG-CuP-COF catalytically produced hydrogen peroxide (H 2 O 2 ) and hydroxyl radicals (•OH) which have important value in triggering acute inflammatory responses and pyroptosis. Moreover, PEG-CuP-COF showed outstanding glutathione peroxidase-mimicking activities, impairing the antioxidant defense in tumor cells and enhancing sonodynamic efficiency by making them more vulnerable to ROS-induced damage. During in vivo studies, PEG-CuP-COF@∆St nanosystem with its self-driven property exhibited impressive tumor-targeting capability and activated Caspase-3/gasdermin E-dependent pyroptosis to inhibit tumor growth. More importantly, it induced a powerful immune memory effect to prevent bone metastasis. In summary, this study introduces an innovative approach for combinatorial sono-catalytic immunotherapy using bacteria-mediated tumor-targeting delivery of nanozymes as specific pyroptosis inducers.