Small extracellular vesicles (EVs) are emerging as crucial mediators of inter-tissue communication. In this presentation, we will describe our recent work which demonstrates that liver-derived EVs play a pivotal role in acute regulation of whole-body glycaemic control in mice. We observed that hyperglycaemia triggers increased secretion of liver EVs into the circulation. These EVs enhance glucose effectiveness and insulin secretion through direct signalling to skeletal muscle and pancreas, respectively. Notably, this acute blood glucose lowering effect is preserved in both healthy and obese mice with metabolic-dysfunction associated liver disease (MASLD), despite significant remodelling of the liver-derived EV proteome in obesity. The efficacy of this mechanism was further validated using liver EVs from humans with and without progressive MASLD, suggesting a broad functional conservation of liver EV signalling across species and potential therapeutic applications. Our findings unveil a novel endocrine signalling pathway whereby liver EVs act on peripheral tissues to restore euglycaemia in the postprandial state, offering new insights into metabolic regulation and potential avenues for treating metabolic disorders.