Nanosonodynamic effect-promoted mitochondrial dysfunction augments calcium overload for Gasdermin E-induced pyroptotic antitumor therapy

Pyroptosis, an inflammatory regulated cell death (RCD), can be effectively driven by calcium overload in Gasdermin E (GSDME)-expressed tumor cells, which provides a distinct and effective pathway to activate a strong inflammatory response in treating refractory carcinomas. Inspired by the fact that the mitochondrial Ca2+-buffering capacity can be influenced and even destroyed by reactive oxygen species (ROS), we herein have designed and engineered a nanosonosensitizer (PpIX)-based liposomal nanosystem, which simultaneously co-encapsulated calcium-supplement CaO2 and DNA methyltransferase (DNMT) inhibitor Decitabine (DAC) for inducing pyroptosis in the context of mitochondria dysfunction. Mechanistically, calcium overload can be logically achieved by the synergism of mitochondrial dysfunction with exogenous Ca2+ delivery, which promotes the release of cytochrome c (cyt c), activates CAS-3 cleavage to GSDME into cytotoxic GSDME-N terminals, and then triggers cancer cell pyroptosis. Taken together, a markedly enhanced antitumor efficiency is achieved via synergistic sonodynamic therapy (SDT) and calcium overload for inducing GSDME-dependent pyroptotic tumor therapy, which is expected to provide a distinct cancer-therapeutic modality based on pyroptosis of cancer cells for malignant carcinomas.