Engineering stem cell-based nanotherapeutics to overcome myocardial ischemia-reperfusion injury

Myocardial ischemia reperfusion injury (MIRI) remains a major challenge in the treatment of acute myocardial infarction, as restoration of coronary blood flow often fails to prevent progressive cardiomyocyte loss, adverse ventricular remodeling, and heart failure. The pathological complexity of ischemia reperfusion injury, involving oxidative stress, inflammatory amplification, microvascular dysfunction, and multiple forms of regulated cell death, has limited the clinical success of conventional single target therapies. Stem cell-based approaches offer unique cardioprotective and immunomodulatory potential but are hampered by poor cell survival, limited engraftment, and safety concerns in the hostile post reperfusion microenvironment. Recent advances in nanotechnology have enabled the development of stem cell based nanotherapeutics that overcome these limitations by enhancing targeting, stability, and functional control. This review summarizes the key mechanisms underlying MIRI and critically evaluates emerging stem cell based nanotherapeutic strategies, including nanosystem empowered stem cell therapies, stem cell derived nanovesicles, and stem cell biomimetic nanotherapeutics. By integrating mechanistic insights with engineering innovations, these approaches provide a systems level solution to the multifaceted pathology of ischemia reperfusion injury and hold promise for advancing precision therapies for ischemic heart disease.