Mesenchymal stem cell‐derived exosomes for cardiac repair: Challenges, standardization gaps and a realistic path to clinical translation

Background Cardiovascular diseases remain the leading cause of mortality worldwide, accounting for approximately one‐third of global deaths annually. Despite advances in pharmacological and interventional therapies, the adult mammalian heart exhibits minimal intrinsic regenerative capacity. Mesenchymal stem cell‐derived small extracellular vesicles (MSC‐sEVs), commonly referred to as exosomes, have emerged as a promising cell‐free therapeutic approach for cardiac repair by delivering bioactive molecules that reduce apoptosis, fibrosis and inflammation while promoting angiogenesis. Objective This review critically assesses current production, purification and engineering methods for MSC‐sEVs, highlighting translational challenges and proposing actionable solutions for clinical development. Key findings Preclinical efficacy shows wide variations due to inconsistent isolation methods, dosing protocols and animal models. A standardized potency assay correlating with cardiac functional outcomes is lacking. While completed phase I trials confirm safety, no controlled phase II/III efficacy trials for cardiac indications have been reported. Engineered sEVs demonstrate improved targeting in rodents, but human translation remains unproven. Major barriers include the absence of validated potency assays, GMP‐compatible standardization, and large‐animal efficacy data. Conclusion MSC‐sEVs represent a promising investigational platform requiring substantial methodological advancement before clinical translation. Significant hurdles, particularly the absence of validated potency assays, manufacturing standardization, and controlled efficacy trials, must be overcome before regulatory authorization can realistically be contemplated. The timeline for regulatory approval remains uncertain and depends on successful completion of these prerequisites.