Pan-membrane pyroptosis of liver induced by gasdermin-encoding mRNAs

ABSTRACT Gasdermin (GSDM)-mediated pyroptosis has been extensively visualized in vitro and linked to multiple physiological and pathological processes. However, the in vivo phenotype and clinical outcome of pyroptosis remain undetermined. Here, we sought to profile in vivo pyroptosis using lipid-nanoparticle (LNP)-encapsulated mRNA encoding the pore-forming N-terminal of GSDMD (GSDMDNT). Upon intravenous (IV) injection, robust expression of GSDMDNT led to acute liver damage, systemic inflammation and sudden death, both in mice and non-human primates, which could be reversed by the GSDMD inhibitor disulfiram or glucocorticoids. Imaging techniques revealed that GSDMDNT targeted both plasma membrane and intracellular membranous organelles, causing membrane rupture and organelle swelling, as well as the formation of intracellular membranous vacuoles. Furthermore, heterologous expression of other GSDM members also caused pyroptosis, both in vitro and in vivo, with varying magnitude. These findings provide insights into the dynamic characteristics of pyroptotic organ injury-related diseases and offer the basis for developing GSDM-based therapeutics.