Stem cell-derived extracellular vesicles as immunomodulators: a novel paradigm for post-myocardial infarction repair and regeneration.

Myocardial infarction (MI) initiates a rapid and highly coordinated immune response that is essential for the clearance of necrotic tissue and activation of reparative processes. However, prolonged or dysregulated post-MI inflammation can exacerbate myocardial injury, promote adverse cardiac remodeling, and ultimately contribute to heart failure. Although current therapeutic strategies improve survival and symptom management, they remain limited in their ability to restore lost cardiomyocytes or effectively modulate the post-infarction immune microenvironment. In this context, stem cell-derived extracellular vesicles (EVs) have emerged as promising cell-free therapeutic candidates due to their immunomodulatory, regenerative, and paracrine properties. These nanoscale vesicles carry a diverse cargo of bioactive molecules, including microRNAs, proteins, lipids, and other signaling mediators that regulate intercellular communication and tissue repair. EVs derived from mesenchymal stem cells, cardiac progenitor cells, and induced pluripotent stem cells have demonstrated the ability to modulate key immune pathways by attenuating neutrophil-mediated inflammatory injury, promoting macrophage polarization towards a reparative M2 phenotype, and regulating T-cell responses by suppressing pro-inflammatory activity while enhancing regulatory T-cell function. Collectively, these effects help restore immune homeostasis and reduce adverse cardiac remodeling following MI. Moreover, advances in EVs engineering, cargo modification, and targeted delivery systems may enhance their therapeutic efficacy and translational potential. However, several critical challenges, including large-scale production, cargo heterogeneity, and the lack of standardized protocols for isolation and characterization, still need to be addressed before successful clinical translation. This review summarizes the current understanding of stem cell-derived EVs biology, comparative advantages over conventional and cell-based therapies, and their immunomodulatory mechanisms in post-MI repair. Moreover, it highlights recent innovations and the major challenges that must be addressed for successful clinical translation.