Exosome therapeutics: A paradigm shift in skin repair through multidimensional immunomodulation and biomaterial-driven delivery

Exosomes, nanoscale extracellular vesicles (30-150 nm) carrying bioactive molecules such as proteins, miRNAs, and lipids, are pivotal mediators of skin repair, modulating immune responses, angiogenesis, oxidative stress, and fibroblast function. This review synthesizes the mechanisms and clinical applications of exosomes in treating conditions such as diabetic ulcers, hypertrophic scars, photoaging, psoriasis, and alopecia. Exosomes from mesenchymal stem cells (MSCs), keratinocytes, and engineered sources regulate inflammatory pathways (e.g., NF-κB, IL-17/IL-23), promote angiogenesis through miRNA-mediated VEGF activation (e.g., miR-21-3p, miR-126), activate the NRF2 pathway to mitigate reactive oxygen species (ROS) accumulation, and modulate TGF-β/Smad signaling to reduce pathological scarring. Advanced delivery systems, including gelatin methacryloyl (GelMA) hydrogels, microneedles, and biomaterial scaffolds, enhance exosome stability and tissue penetration. Preclinical and early-phase clinical studies demonstrate accelerated wound healing, reduced scar formation, and enhanced skin regeneration. However, challenges such as standardized production, functional heterogeneity, long-term safety, and regulatory hurdles persist. Emerging technologies, such as single-exosome sequencing and artificial intelligence, offer solutions to optimize exosome therapy. As a promising cell-free therapeutic approach, exosomes require interdisciplinary collaboration to ensure efficacy and safety for clinical translation.