Small Extracellular Vesicles in Cardioprotection, Cardiac Repair, and Regeneration: Cargo Mechanisms, Producer Cell Sources, and Translational Development

Cardiovascular diseases remain a major cause of death and disability, and the limited regenerative capacity of the adult myocardium continues to constrain recovery after myocardial infarction, ischemia/reperfusion injury, cardiomyopathy, and heart failure. Small extracellular vesicles (sEVs), often described as exosome-enriched vesicle preparations, have emerged as promising cell-free mediators of cardioprotection and cardiac repair. This review evaluates the current experimental and translational evidence on sEVs in cardiac injury, including regulatory RNA and non-RNA cargo mechanisms, producer cell sources, preclinical injury models, engineered and biomaterial-assisted delivery strategies, and the development of clinically viable cell-free therapies. Across preclinical models, sEVs derived from mesenchymal stem cells, induced pluripotent stem cell-derived cardiac cells, cardiac progenitor cells, endothelial cells, cardiomyocytes, immune cells, and other sources have been associated with improved ventricular function, reduced infarct or scar size, enhanced angiogenesis, lower apoptosis, attenuated fibrosis, and modulation of post-injury inflammation. These effects are frequently associated with changes in, or enrichment of, microRNAs, long non-coding RNAs, and circular RNAs that regulate survival signaling, immune polarization, extracellular matrix remodeling, and endothelial recovery. Emerging evidence further suggests that proteins, lipids, and organelle-associated cargo, including mitochondrial components, also contribute to stress adaptation, vesicle biogenesis, mitochondrial homeostasis, and metabolic repair. However, the field remains limited by inconsistent nomenclature, variable isolation and characterization methods, heterogeneous producer cell sources, uncertain potency assays, incomplete biodistribution data, and unresolved regulatory classification. Overall, sEV-based therapy represents a compelling but still developing approach to cardiac repair. Within this framework, functional recovery is treated as an outcome of cardioprotection, cardiac repair, or, where supported, myocardial regeneration; regeneration is reserved for evidence of newly formed and functionally integrated myocardium. Future progress will depend on better product definition, mechanism-linked potency testing, scalable manufacturing, and delivery strategies matched to specific cardiac indications.