Pyroptosis promotes antitumor immunity, yet its efficacy is often constrained by the reliance on indirect signaling cascades, intrinsic cytoprotective mechanisms, and the frequent silencing of gasdermin (GSDM) expression in tumor cells. Here, we develop a precise strategy for activating tumor pyroptosis through the targeted delivery of genetically engineered attenuated Salmonella typhimurium (eVNP, a strain designed to express GSDMD-NT). This platform integrates Near-Infrared (NIR)-triggered pyroptosis induction with Pd0-catalyzed autophagy inhibition, thereby achieving spatiotemporal precision and amplified tumor cell death. The eVNP is camouflaged with a hybrid membrane composed of palladium-mineralized tumor... More
Pyroptosis promotes antitumor immunity, yet its efficacy is often constrained by the reliance on indirect signaling cascades, intrinsic cytoprotective mechanisms, and the frequent silencing of gasdermin (GSDM) expression in tumor cells. Here, we develop a precise strategy for activating tumor pyroptosis through the targeted delivery of genetically engineered attenuated Salmonella typhimurium (eVNP, a strain designed to express GSDMD-NT). This platform integrates Near-Infrared (NIR)-triggered pyroptosis induction with Pd0-catalyzed autophagy inhibition, thereby achieving spatiotemporal precision and amplified tumor cell death. The eVNP is camouflaged with a hybrid membrane composed of palladium-mineralized tumor cell membranes and vesicular stomatitis virus glycoprotein (VSV-G)-expressing HEK293T cell membranes. This hybrid coating confers homotypic tumor targeting, immune evasion, and pH-responsive membrane fusion, facilitating cellular internalization. Upon NIR irradiation, a heat-inducible promoter drives GSDMD-NT expression, leading to bacterial self-lysis and the subsequent release of GSDMD-NT into the cytoplasm to initiate pyroptosis. Concurrently, Pd0-catalyzed bioorthogonal reaction activates autophagy inhibitors, suppressing autophagy and amplifying pyroptotic cell death. In vivo, this system achieves tumor suppression and reprograms the immunosuppressive tumor microenvironment, offering a robust and integrative strategy for advancing cancer immunotherapy.
