Invoking the occurrence of pyroptosis is an emerging strategy for the treatment of cancer. However, the practical applications of pyroptosis for cancer therapy are currently hindered due to the lack of tumor‐specific and efficient pyroptotic agents in vivo. Herein, a virus‐spike tumor‐activatable pyroptotic agent (VTPA) for cancer‐specific therapy is reported. The VTPA is composed of an organosilica coated iron oxide nanoparticle core and spiky manganese dioxide protrusions, which can readily accumulate in tumor after systemic administration, facilitate the tumor intracellular lysosomal rupture, and be degraded by tumor over‐expressed intracellular glutathione (GSH) to release Mn ions and iron oxide nanoparticles (IONPs) for the synergetic activation of nucleotide binding oligomerization domain‐like receptors protein 3 (NLRP3) inflammasomes. Consequently, the activation of NLRP3 inflammasomes and the release of lactate dehydrogenase of tumor cells are observed after the treatment of VTPA, resulting in a specific pyroptotic cell death. To our best knowledge, the structure‐dependent and tumor intracellular GSH activatable pyroptotic agents represent the first demonstration of cancer‐specific pyroptosis in vivo, providing a novel paradigm for the development of next‐generation cancer‐specific pyroptotic nanomedicine.

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