TITLE:
Exosome-Mediated Regulation of Macrophages in Myocardial Ischemia-Reperfusion Injury: Mechanisms and Therapeutic Perspectives
AUTHORS:
Zhibin Zhang, Wenqing Gao
KEYWORDS:
Exosomes, Macrophage Polarization, Myocardial Ischemia-Reperfusion Injury, Inflammation, Cell-Free Therapy
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.14 No.5,
May
29,
2026
ABSTRACT: Myocardial ischemia-reperfusion injury (MIRI) remains a major unresolved problem in the treatment of acute myocardial infarction and other clinical conditions requiring restoration of coronary blood flow. Although timely reperfusion is essential for salvaging ischemic myocardium, the abrupt reintroduction of oxygen and nutrients can paradoxically aggravate myocardial injury through oxidative stress, calcium overload, mitochondrial dysfunction, endothelial damage, and sterile inflammation. Among the immune cells involved in this process, macrophages play a central and dynamic role. In the early phase of reperfusion, pro-inflammatory macrophages amplify tissue injury by releasing cytokines, chemokines, reactive oxygen species, and inflammasome-related mediators. During the reparative phase, macrophages gradually acquire anti-inflammatory and tissue-repairing features, contributing to efferocytosis, angiogenesis, extracellular matrix remodeling, and functional recovery. Therefore, regulating macrophage phenotype and function has emerged as a promising strategy for the treatment of MIRI. Exosomes, more broadly referred to as small extracellular vesicles when their biogenesis has not been strictly demonstrated, are nanoscale membrane vesicles secreted by multiple cell types. They carry bioactive molecules, including microRNAs, long non-coding RNAs, proteins, lipids, and metabolites, and mediate intercellular communication in physiological and pathological settings. Accumulating evidence indicates that exosomes derived from mesenchymal stem/stromal cells, macrophages, cardiomyocytes, and other cell types can regulate macrophage polarization and inflammatory responses in MIRI. Specific exosomal cargos, such as miR-148a, miR-182, miR-21-5p, miR-25-3p, and miR-125a-5p, have been implicated in the modulation of TXNIP, TLR4/NF-κB/NLRP3, PI3K/Akt, JAK/STAT, and related signaling pathways. These findings suggest that exosome-based therapy may provide a cell-free, immunomodulatory, and targeted approach for myocardial protection. This review summarizes the pathophysiological role of macrophages in MIRI, the biological characteristics of exosomes, the molecular mechanisms by which exosomes regulate macrophage function, and the translational challenges that must be addressed before clinical application.