Therapeutic landscape of stem cell‑derived exosomes: Mechanisms, disease applications, and translational challenges

The clinical translation of direct stem-cell transplantation has been hampered by immune rejection, tumorigenicity, poor engraftment efficiency, and manufacturing complexity. Accumulating mechanistic evidence indicates that the regenerative and antiinflammatory benefits of stem cells are mediated primarily through their paracrine output, in particular the release of exosomes. These 30–150-nm lipid bilayer vesicles carry a sophisticated cargo of proteins, lipids, messenger RNAs, long noncoding RNAs, circular RNAs, and microRNAs that reprogram recipient cells along multiple converging pathways. Three mechanistic pillars define the therapeutic identity of stem cell‑derived exosomes (SC-Exos). First, immunomodulation: SC-Exos shift macrophage and microglial polarization from the proinflammatory M1 to the reparative M2 phenotype, suppress NLRP3 inflammasome activation, and restore lymphocyte subset balance. Second, regulation of programmed cell death: SC-Exos inhibit apoptosis, pyroptosis, and the iron-dependent ferroptosis pathway via the Nrf2/GPX4/SLC7A11 and PINK1/Parkin mitophagy axes. Third, promotion of tissue regeneration: SC-Exos stimulate angiogenesis, neurogenesis, and mitochondrial quality control through organelle cargo transfer. Exploiting these converging mechanisms, SC-Exos have demonstrated compelling preclinical efficacy in central nervous system injuries (traumatic brain injury and spinal cord injury); cerebrovascular diseases (ischemic stroke and intracerebral hemorrhage); neurodegenerative conditions (Alzheimer’s and Parkinson’s diseases); respiratory diseases (acute lung injury, chronic obstructive pulmonary disease (COPD), and viral pneumonia); digestive diseases (colitis and gastric cancer); and emerging indications in nephritis, myocarditis, and antiaging medicine. Early-phase clinical observations in COVID-19 pneumonia and COPD have validated the human safety profile. Nevertheless, significant barriers persist: batch-to-batch cargo variability driven by producer-cell culture conditions, the absence of good manufacturing practice grade standardization protocols, unresolved pharmacokinetic questions, and a sparse randomized clinical trial evidence base. This review synthesizes the mechanistic and translational literature, critically appraises discordant findings and methodological limitations, and proposes a strategic roadmap for advancing SC-Exos toward clinical practice.