Mechanisms of skin wound healing regulated by fibroblast-derived exosomes

Skin wound healing is a complex and highly coordinated biological process involving multiple cell types and signaling pathways, among which fibroblasts play a pivotal role. Exosomes, as nanoscale extracellular vesicles that mediate intercellular communication, have emerged as critical regulators in tissue repair. This review summarizes the biological characteristics of fibroblast-derived exosomes and their regulatory roles and molecular mechanisms in skin wound healing. Fibroblast exosomes accelerate wound closure by promoting cell proliferation and migration, modulating inflammatory responses, enhancing angiogenesis, and remodeling the extracellular matrix (ECM). Their cargo—comprising bioactive molecules such as microRNAs (miRNAs), proteins, and growth factors—participates in multiple signaling pathways including TGF-β/Smad, PI3K/Akt, and NF-κB, thereby orchestrating cellular behaviors essential for effective tissue regeneration. Specific miRNAs, such as miR-21, miR-29, and miR-146a, have been identified as key mediators regulating fibroblast differentiation, ECM synthesis, and inflammatory resolution. Furthermore, fibroblast exosomes exhibit considerable potential in clinical applications, including chronic wound treatment, tissue engineering, regenerative medicine, and drug delivery systems, owing to their low immunogenicity and intrinsic bioactivity. Despite these advances, challenges remain in the standardization, large-scale production, and safety evaluation of exosome-based therapies. Future studies focusing on elucidating exosome heterogeneity, optimizing biomanufacturing processes, and ensuring clinical safety will be crucial to translating fibroblast-derived exosomes into effective therapeutic agents. Collectively, fibroblast exosomes represent a promising cell-free strategy for promoting wound healing and advancing regenerative medicine. • Comprehensive overview of fibroblast-derived exosomes in wound healing. • Integrates molecular mechanisms with translational and therapeutic insights. • Highlights key signaling pathways including TGF-β/Smad, PI3K/Akt, and NF-κB. • Addresses challenges of exosome heterogeneity, production, and clinical safety. • Provides a forward-looking framework for regenerative and personalized medicine.