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

Abstract 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.