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Chronically elevated circulating excess free fatty acids (i.e. lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven Type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-³¦±ð±ô±ôs by reducing glucose-stimulated insulin secretion (GSIS), altering β-³¦±ð±ô±ô transcriptional identity, and promoting apoptosis. While β-³¦±ð±ô±ô-derived small extracellular vesicles (sEV) have been shown to contribute to β-³¦±ð±ô±ô failure in T2D, their specific role in lipotoxicity-mediated β-³¦±ð±ô±ô failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-³¦±ð±ô±ôs, which exhibit altered proteomic and lipidomic profiles. These PAL EV induce β-³¦±ð±ô±ô dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved PAL EV-induced β-³¦±ð±ô±ô dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-³¦±ð±ô±ô sEVs and implicated their role in inducing β-³¦±ð±ô±ô functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-³¦±ð±ô±ô health in metabolic disorders.