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.