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

A self-priming pyroptosis-inducing agent (MnNZ@OMV) is engineered by integrating manganese dioxide nanozymes (MnNZ) with outer membrane vesicles (OMVs). Upon internalization, MnNZ@OMV releases Mn²⁺ to generate ROS. This triggers NF-κB nuclear translocation, priming caspase-11 expression, while OMVs concurrently activate caspase-11 to cleave GSDMD, thereby inducing pyroptosis. This cascade potentiates robust anti-tumor immunity, representing a novel strategy for enhancing cancer immunotherapy.

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 Mn²⁺ and OMV components. This leads to GSH depletion and Mn²⁺-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.