Our research underscores the immense potential of Mesenchymal Stem Cells (MSCs) soluble and insoluble paracrine factors in the rapidly advancing cell-free therapy approach for myocardial repair. Exosomes with specific cargo and secretomes, the entire set of soluble factors released by cells as part of their paracrine activity, are pivotal in this process. Their potential as novel therapeutic agents is promising, instilling hope and opening up a new horizon in myocardial repair and regeneration.

In this review, we meticulously conducted a comprehensive literature-based approach using multiple databases, i.e., PubMed, Science Direct, Google Scholar, SpringerLink, Cochrane Library, ClinicalTrials.gov, and Semantic Scholar. Our search terms were carefully selected and combined to identify 309 relevant studies for inclusion, of which 42 were preclinical and clinical trials. We delved into the immunogenicity of exosomal cargo, molecular signaling pathways, myocardial repair, and the role of secretomes as novel therapeutic agents. We also reviewed the clinical applications of secretome and exosome-mediated targeted drug delivery systems.

The safety and efficacy of exosomes and secretomes in enhancing cardiac function post-MI in small and large animal models were primarily derived from BM-MSCs. Both exosome and secretome-based treatments significantly improve myocardial functionality parameters such as LVEF and LVFS, reduce infarct size, and enhance angiogenesis in experimental animal models in a dose-dependent manner. They demonstrated modulation of inflammatory response and promoted intrinsic stem cell homing-in to participate in myocardial repair. Exosomes have also been modulated for targeted delivery of cargo of interest. Phase-I clinical studies (Clinicaltrial.gov ID: NCT05669144 & NCT05774509) are underway, providing reassurance and confidence in their potential efficacy in clinical settings.

In conclusion, exosomes offer targeted delivery of therapeutic cargo, while secretomes provide a broader spectrum of reparative factors. Further research is needed to understand the mechanisms of action and define the pharmacokinetics of these novel therapeutic options.