Clinical applications of stem cell-derived exosomes

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TL;DR

This review comprehensively summarizes the therapeutic potential of stem cell-derived exosomes (SC-Exo) across a wide range of surgical specialties, including orthopedics, neurosurgery, plastic surgery, and ophthalmology. SC-Exo, particularly from mesenchymal stem cells (MSCs) and neural stem cells (NSCs), demonstrate comparable therapeutic effects to their parental cells—such as tissue regeneration, anti-inflammation, and immunomodulation—without the risks of tumorigenicity or ethical concerns. The clinical significance lies in the potential of SC-Exo as a safer, cell-free alternative for treating conditions like fractures, osteoarthritis, spinal cord injury, ischemic stroke, and wound healing, with several clinical trials already underway.

Full summary

4,278 CHARS

**Background:** Stem cell-based therapy has shown promise for regenerative medicine but faces limitations including infusion toxicity, immunogenicity, tumorigenic potential, and ethical issues. Exosomes, nanoscale extracellular vesicles secreted by stem cells, have emerged as a safer alternative, inheriting therapeutic effects such as anti-inflammation, immunomodulation, and tissue regeneration from their parental cells. This review aims to provide a comprehensive, specialty-specific overview of the downstream clinical applications of stem cell-derived exosomes (SC-Exo) in surgical practice, bridging the gap between surgeons, nanomedicine practitioners, and stem cell researchers.

**Methods:** The authors conducted a narrative review of publications from the last five years, focusing on the downstream surgical applications of SC-Exo. The review covers exosome biogenesis, composition, isolation, modification, and characterization, followed by a disease-oriented analysis across multiple surgical specialties. The paper synthesizes findings from preclinical studies and clinical trials, with a search on ClinicalTrials.gov identifying 188 records related to exosomes, of which 60 were interventional studies using exosomes as therapeutic agents.

**Key Results:** The review details the therapeutic potential of SC-Exo in numerous surgical fields: - **Orthopedic and Trauma Surgery:** In fracture healing, bone marrow MSC-derived exosomes promoted osteogenesis and angiogenesis via pathways like BMP-2/Smad1/RUNX2 and Wnt/β-catenin. For osteoarthritis, MSC-derived exosomes (e.g., from infrapatellar fat pads) protected cartilage via miR-100-5p and inhibited inflammation. In spinal cord injury, NSC-derived exosomes reduced lesion size and promoted functional recovery through mechanisms including miR-219a-2-3p/YY1 pathway and M2 macrophage polarization. For muscle and tendon tears, MSC-derived exosomes improved myogenesis and tendon healing. - **Neurosurgery:** In ischemic stroke, NSC-derived exosomes reduced infarction area and neuronal apoptosis (e.g., via miR-150-3p). For traumatic brain injury, MSC-derived exosomes improved spatial learning and sensorimotor function in rats, monkeys, and swine models. In Alzheimer's disease, MSC-derived exosomes reduced Aβ plaque burden and improved cognitive function. For Parkinson's disease, NSC-derived exosomes protected dopaminergic neurons via miR-182-5p and miR-183-5p. - **Plastic Surgery:** MSC-derived exosomes accelerated cutaneous wound healing by promoting angiogenesis (e.g., via Akt/eNOS pathway), proliferation of fibroblasts and keratinocytes, and reducing scar formation through TGF-β/Smad2 pathway inhibition. - **General Surgery:** MSC-derived exosomes protected against acute liver injury by stabilizing SLC7A11 and ameliorated liver fibrosis via circDIDO1/miR-141-3p/PTEN/Akt pathway. - **Cardiothoracic Surgery:** MSC-derived exosomes alleviated myocardial infarction by targeting pro-apoptotic proteins (e.g., miR-25-3p) and reduced myocardial ischemia-reperfusion injury via JAK/STAT pathway. - **Ophthalmology:** MSC-derived exosomes promoted retinal ganglion cell survival in optic nerve crush models, and NSC-derived exosomes preserved photoreceptors in retinal degeneration models. - **Obstetrics and Gynecology:** Umbilical cord MSC-derived exosomes restored ovarian function in primary ovarian insufficiency models via Hippo pathway and miR-17-5p.

Clinical trials (60 interventional studies) have explored SC-Exo for conditions including COVID-19 (16 trials), cancer (5 trials), osteoarthritis, ischemic stroke, and Alzheimer's disease. Most trials (95%) used MSC-derived exosomes, with a few using iPSC-derived exosomes.

**Clinical Implications:** SC-Exo therapy represents a potent, versatile, and safer surrogate for stem cell therapy, avoiding risks of tumorigenesis and immune rejection. The review highlights the need for standardized production protocols, scalable manufacturing (e.g., bioreactors), and multimodal delivery systems (e.g., biomaterial scaffolds) to translate preclinical success into clinical practice. Future research should expand indications to include airway inflammatory diseases, surgical implant-related conditions, and anesthesia-related complications.