A Self‐Priming Pyroptosis‐Inducing Agent for Activating Anticancer Immunity

Abstract Pyroptosis, a form of programmed cell death mediated by the gasdermin family, has emerged as a promising strategy for inducing anti‐tumor immunity. However, efficiently inducing pyroptosis in tumor cells remains a significant challenge due to the limited activation of key mediators like caspases in tumor tissues. Herein, a self‐priming pyroptosis‐inducing agent (MnNZ@OMV) is developed by integrating outer membrane vesicles (OMVs) with manganese dioxide nanozymes (MnNZ) to trigger pyroptosis in tumor cells. OMVs, derived from Escherichia coli , are coated onto spiny MnNZ to prepare MnNZ@OMV. Once internalized by tumor cells, MnNZ@OMV responds to elevated intracellular glutathione (GSH) levels, releasing Mn 2 ⁺ and OMV components. This leads to GSH depletion and Mn 2 ⁺‐catalyzed reactive oxygen species generation, which triggers NF‐κB translocation and prime caspase‐11 expression. Subsequently, lipopolysaccharides from OMVs activate caspase‐11, resulting in GSDMD cleavage and pyroptosis induction. MnNZ@OMV significantly induces tumor pyroptosis in vivo, promoting dendritic cell maturation and CD8⁺ T cell activation, leading to robust anti‐tumor effects. Collectively, this study presents a novel self‐priming approach for inducing tumor cell pyroptosis through the noncanonical caspase‐11/GSDMD pathway, offering a promising avenue for future cancer immunotherapy.