Apoptotic Extracellular Vesicles (ApoEVs) Safeguard Liver Homeostasis and Regeneration <i>via</i> Assembling an ApoEV-Golgi Organelle

Summary Apoptosis is an integral physiological cell death process that occurs frequently and generates a huge number of apoptotic extracellular vesicles (apoEVs). However, whether apoEVs are necessary for maintaining organ homeostasis remains unclear. Here, we show that circulatory apoEVs engraft in liver and undergo specialized internalization by hepatocytes (HCs) based on surface signature of galactose and N -acetylgalactosamine. Furthermore, apoEVs rescue liver injury in apoptotic-deficient Fas mutant and Caspase-3 knockout mice, which is exerted by restoring the featured hepatic ploidy homeostasis. Surprisingly, apoEVs form a chimeric organelle complex with recipient Golgi apparatus via SNARE-mediated membrane interaction, which consequently facilitates microtubule organization and HC cytokinesis. Notably, through Golgi recovery and ploidy transition, apoEVs contribute to liver regeneration and protect against acute hepatic failure. Collectively, these results identify a previously unrecognized role for apoEVs and the specific mechanisms by which they safeguard liver homeostasis, and suggest the potential of apoEV-based therapy for liver disorders.