An Adiponectin Receptor Agonist Dispersed via Nonencapsulative Exosomes Alleviates Aging-Associated Cardiac Dysfunction.

Aging-related cardiac dysfunction constitutes a major and growing global health challenge with limited effective treatment options. 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-endoplasmic 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.