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While adiponectin receptor activation has demonstrated cardioprotective potential, its translation into a viable therapy for the senescent heart remains unrealized. In this study, we developed CardiAdip (CAD), an agonist with improved predicted binding affinity for adiponectin receptors. In d-galactose (d-gal)-induced senescent H9c2 cardiomyocytes, CAD attenuated senescence-associated phenotypes and reduced stress-responsive signaling. In naturally aged mice (24 months), oral administration of CAD significantly improved cardiac function, alleviated myocardial hypertrophy and fibrosis, and suppressed molecular hallmarks of cardiac aging. Transcriptomic and molecular analyses indicated that these benefits were mediated through the restoration of mitochondrial\u2013endoplasmic reticulum homeostasis and the alleviation of oxidative stress in aged myocardium. To enable effective systemic administration, we reformulated CAD into a stable aqueous dispersion (CAD-cluster) via exosome-assisted nonencapsulative dispersion. This approach expanded the administration route to intravenous injection and significantly enhanced systemic exposure. Remarkably, intravenous administration of CAD-cluster achieved therapeutic efficacy comparable to high-dose oral CAD while requiring a markedly reduced cumulative dose. Together, these findings identify CAD as an effective therapeutic candidate for aging-related cardiac dysfunction and support nonencapsulative exosome-assisted dispersion as a practical strategy to improve the translational feasibility of poorly soluble membrane-targeted small molecules.<\/jats:p>","DOI":"10.1021\/acsami.6c08909","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:02:26Z","timestamp":1787241746000},"page":"46043-46064","source":"Crossref","is-referenced-by-count":0,"title":["An Adiponectin Receptor Agonist Dispersed via Nonencapsulative Exosomes Alleviates Aging-Associated Cardiac Dysfunction"],"prefix":"10.1021","volume":"18","author":[{"given":"Yin","family":"Zhou","sequence":"first","affiliation":[{"name":"the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510120"]},{"name":"Guangzhou National Laboratory , No. 9 XingDaoHuanBei Road , , ,","place":["Guangzhou, Guangdong, China, 510005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, SAR, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilei","family":"Wang","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penghui","family":"Zeng","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510120"]},{"name":"Guangzhou National Laboratory , No. 9 XingDaoHuanBei Road , , ,","place":["Guangzhou, Guangdong, China, 510005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhu","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510120"]},{"name":"Guangzhou National Laboratory , No. 9 XingDaoHuanBei Road , , ,","place":["Guangzhou, Guangdong, China, 510005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, SAR, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9000-7016","authenticated-orcid":true,"given":"Xifei","family":"Yang","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Disease Control and Prevention , , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhao","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macau, SAR, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushuo","family":"Feng","sequence":"additional","affiliation":[{"name":"Jinfeng Laboratory , , ,","place":["Chongqing, China, 401329"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1155-8547","authenticated-orcid":true,"given":"Ming","family":"Dong","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , , , ,","place":["Guangzhou, Guangdong, China, 510120"]},{"name":"Guangzhou National Laboratory , No. 9 XingDaoHuanBei Road , , ,","place":["Guangzhou, Guangdong, China, 510005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"issue":"10","key":"2026101216070456600_cit1","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1161\/CIRCRESAHA.121.318172","article-title":"Epidemiology of Heart Failure: A Contemporary Perspective","volume":"128","author":"Roger","year":"2021","journal-title":"Circ. 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