Skin organoid-derived exosomes in a hydrogel system potentiate skin wound healing.

Skin wounds, whether acute or chronic, remain a major clinical challenge due to their complex healing processes involving inflammation, angiogenesis, and tissue remodeling. While stem cell-derived exosomes offer a promising cell-free therapeutic approach, their clinical translation is limited by rapid clearance and insufficient tissue-specificity. In this study, we developed a novel strategy by integrating exosomes derived from skin organoids (SKO-Exo)-which mimic native skin heterogeneity-into a hydrogel-based sustained-release system (Exo-Gel) to enhance wound healing. Skin organoids were generated from human embryonic stem cells, and exosomes were isolated and characterized, revealing typical cup-shaped morphology and exosomal markers. The hydrogel, composed of polyvinyl alcohol/gelatin/boric acid, exhibited excellent self-healing, adhesion, and sustained exosome release with an initial burst. In vitro, SKO-Exo-loaded hydrogel (SKOexo-Gel) significantly promoted endothelial cell proliferation, migration, and tube formation, as well as fibroblast collagen III secretion, outperforming exosomes from 3D keratinocytes (KC-Exo). In a rat full-thickness wound model, SKOexo-Gel accelerated wound closure, enhanced angiogenesis, and increased collagen III deposition. miRNA sequencing identified Hsa-miR-125b-5p as a prominent SKO-Exo-enriched miRNA that activates the Wnt/β-catenin pathway to drive angiogenesis, validated by functional assays. These findings demonstrate that skin organoid-derived exosomes in a hydrogel system synergistically promote wound healing through tissue-specific cues, offering a next-generation therapy for refractory wounds.