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Extracellular vesicles (EVs) mediate intercellular communication in cardiac pathophysiology. Adiponectin mediates cardioprotective effects yet its relationship with EVs biology remains unexplored. We investigated whether ALY688, an adiponectin receptor agonist, modulates EV biogenesis and cargo to confer cardioprotection in a mouse model of myocardial infarction (MI). ALY688 (15\u00a0mg\/kg daily for 28 days) significantly attenuated MI\u2010induced cardiac dysfunction, reduced infarct size, and decreased fibrotic scar in both lean mice on standard chow and obese mice fed a high\u2010fat diet. Plasma EVs were isolated and while MI reduced circulating EV numbers, ALY688 restored EV production and enhanced loading with bioactive adiponectin. In addition, proteomic analysis revealed ALY688\u2010shaped EVs were enriched in metabolism regulated proteins. The direct functional effects and mechanisms of EV action were examined in iPSC\u2010derived cardiomyocytes and H9c2 cells. EV from ALY688 treated mice (EV\n                    <jats:sup>ALY<\/jats:sup>\n                    ) reduced hypoxia\u2010induced apoptosis, cell death, and ROS accumulation while restoring mitochondrial function and enhancing autophagy flux, whereas EV from control mice did not. Importantly, intervention with systemic EV\n                    <jats:sup>ALY<\/jats:sup>\n                    administration to mice reduced post\u2010MI plasma troponin I and LDH levels, decreased apoptosis, and improved mitochondrial dynamics. Thus, we show that ALY688 enhances EV\u2010mediated cardioprotection through multiple cellular mechanisms including adiponectin delivery, oxidative stress reduction, autophagy restoration, and mitochondrial recovery. These findings provide preclinical evidence supporting the feasibility of evidence for harnessing endogenous repair mechanisms through EVs modulation to mitigate acute cardiovascular injury.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202505837","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T07:41:41Z","timestamp":1776152501000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Extracellular Vesicles Modulation by an Adiponectin Receptor Agonist Provides Cardioprotection for Myocardial Ischemic Injury"],"prefix":"10.1002","volume":"15","author":[{"given":"Jialing","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Biology York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing Yan","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Biology York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena M.","family":"Pulente","sequence":"additional","affiliation":[{"name":"The Department of Biochemistry, Microbiology and Immunology Faculty of Medicine The University of Ottawa Heart Institute Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Biology York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khang","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biology York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddie","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Biology York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadya M.","family":"Morrow","sequence":"additional","affiliation":[{"name":"The Department of Biochemistry, Microbiology and Immunology Faculty of Medicine The University of Ottawa Heart Institute Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Lorenzen\u2010Schmidt","sequence":"additional","affiliation":[{"name":"The Department of Biochemistry, Microbiology and Immunology Faculty of Medicine The University of Ottawa Heart Institute Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxia","family":"Xiao","sequence":"additional","affiliation":[{"name":"Kidney Research Center Department of Cellular and Molecular Medicine The Ottawa Hospital Research Institute The University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augusto","family":"Zani","sequence":"additional","affiliation":[{"name":"Developmental and Stem Cell Biology Program Peter Gilgan Centre For Research and Learning The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan","family":"Burger","sequence":"additional","affiliation":[{"name":"Kidney Research Center Department of Cellular and Molecular Medicine The Ottawa Hospital Research Institute The University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Kyoung","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Biology York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin E.","family":"Mulvihill","sequence":"additional","affiliation":[{"name":"The Department of Biochemistry, Microbiology and Immunology Faculty of Medicine The University of Ottawa Heart Institute Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1946-1347","authenticated-orcid":false,"given":"Gary","family":"Sweeney","sequence":"additional","affiliation":[{"name":"Department of Biology York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad380"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001052"},{"key":"e_1_2_12_4_1","first-page":"62","article-title":"Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment","volume":"106","author":"Azevedo P. 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