Cell-free therapeutics for non-healing wounds: role of MSC-derived exosomes in macrophage polarization, angiogenesis, and fibroblast-mediated ECM remodeling-bridging preclinical insights to clinical translation.

Non-healing wounds, such as diabetic foot ulcers, burns, and pressure injuries, represent a persistent clinical challenge, affecting an estimated 2-5% of the global population and accounting for annual healthcare costs exceeding USD 25 billion. Their failure to heal is driven by unresolved inflammation, inadequate vascularization, and progressive disorganization of extracellular matrix (ECM) architecture, which collectively disrupt the coordinated cascade of tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes have emerged as a potent cell-free therapeutic approach capable of addressing these pathological barriers through multi-level biological modulation of immune, vascular, and stromal compartments. Preclinical studies demonstrate that topical or injectable administration of MSC-derived exosomes accelerates wound closure by 25-60% within 10-14 days compared to controls. Immunomodulatory effects include promoting macrophage polarization from M1 to M2 phenotypes, with reported increases in M2/M1 ratios of 1.5-3.2-fold, mediated by exosomal miRNAs (e.g., miR-223, miR-181c) and proteins that suppress NF-κB signaling. Angiogenesis is markedly enhanced, with microvascular density rising by 30-70%, driven by the transfer of VEGF, miR-126, and miR-21 to endothelial cells, thereby boosting migration and tube formation. Fibroblast activity is similarly upregulated, resulting in 1.4-2.0-fold increases in collagen deposition and restoration of the MMP/TIMP balance, leading to improved tensile strength and ECM integrity. Integration of biomaterial-assisted delivery platforms, including thermosensitive hydrogels, collagen scaffolds, and microneedle arrays, extends exosome retention and functional bioavailability at the wound site by 2-5 times compared to free vesicles. While early clinical trials report safety and feasibility, challenges in large-scale GMP manufacturing, batch-to-batch consistency, and regulatory harmonization. Overcoming these translational barriers through advances in bioengineering, genetic modification, and smart delivery systems may enable the evolution of MSC-derived exosomes into standardized, next-generation therapeutics for chronic, non-healing wounds.