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In obesity, hypertrophic adipocytes, pro-inflammatory macrophages, and dysfunctional endothelial cells secrete EVs carrying altered cargo, including pro-inflammatory miRNAs (e.g., miR-34a, miR-155), bioactive lipids, and stress proteins, which propagate systemic metabolic dysfunction. Adipose tissue-derived EVs impair hepatic fatty acid oxidation, promote steatohepatitis, suppress pancreatic beta-cell insulin secretion, induce skeletal muscle insulin resistance via PPAR\u03b3 repression, and contribute to endothelial dysfunction and atherosclerosis. EV-mediated adipocyte\u2013macrophage crosstalk reinforces chronic adipose inflammation. Circulating EVs also provide biomarkers: subpopulation ratios, miRNA signatures, and tissue factor-positive EVs reflect disease severity, predict cardiovascular risk, and monitor therapeutic responses, with machine learning enhancing diagnostic precision. Therapeutically, EVs from mesenchymal stem cells, Wharton\u2019s jelly MSCs, adipose progenitors, and M2 macrophages reverse insulin resistance, hepatic steatosis, and adipose inflammation in preclinical models. Engineering strategies improve EV potency and tissue targeting, and Phase I trials confirm safety, though manufacturing and cost remain barriers. Preclinical and early clinical studies of MSC-EVs confirm a favorable safety profile, though manufacturing scalability and cost remain barriers to widespread clinical adoption. Overall, EVs represent both diagnostic tools and therapeutic vehicles in precision obesity medicine, offering a pathway from symptom management toward true disease remission.<\/jats:p>","DOI":"10.3390\/ijms27073137","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T15:20:47Z","timestamp":1774884047000},"page":"3137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Extracellular Vesicles in Obesity: From Pathophysiological Mediators to Therapeutic Tools"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3452-389X","authenticated-orcid":false,"given":"Nikola","family":"Pavlovi\u0107","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia"},{"name":"Laboratory for Cardiometabolic Research, University of Split School of Medicine, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6953-0135","authenticated-orcid":false,"given":"Petar","family":"Todorovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-7597","authenticated-orcid":false,"given":"Mirko","family":"Maglica","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina"},{"name":"Department of Otorhinolaryngology, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Kopila\u0161","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Health Center Mostar, 88000 Mostar, Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roko","family":"\u0160anti\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia"},{"name":"Laboratory for Cardiometabolic Research, University of Split School of Medicine, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9696-3359","authenticated-orcid":false,"given":"Marko","family":"Kumri\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia"},{"name":"Laboratory for Cardiometabolic Research, University of Split School of Medicine, 21000 Split, Croatia"},{"name":"Department of Cardiovascular Diseases, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marino","family":"Lukenda","sequence":"additional","affiliation":[{"name":"Ministry of Defence of the Republic of Croatia, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1634-0635","authenticated-orcid":false,"given":"Jo\u0161ko","family":"Bo\u017ei\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia"},{"name":"Laboratory for Cardiometabolic Research, University of Split School of Medicine, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nowicka, G. 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