Tremella fuciformis-derived extracellular vesicles promote cutaneous regeneration through modulation of inflammatory microenvironment and regenerative responses.

The clinical translation of extracellular vesicle (EV)-based therapies is currently hindered by the high manufacturing costs and limited scalability of conventional mammalian cell sources. Edible fungus-derived EVs have emerged as a promising alternative with potential advantages in scalability and cost-effectiveness. Here, we investigated the therapeutic potential of EVs derived from Tremella fuciformis fermentation broth (TFB-EVs) for cutaneous wound healing. In a murine full-thickness wound model, TFB-EV treatment significantly accelerated wound closure, reducing the residual wound area to 6.87 ± 2.95% by day 14, compared with 21.63 ± 4.82% in the control group (p < 0.001). Histological analysis confirmed improved tissue quality, characterized by enhanced re-epithelialization and more organized collagen deposition. Functionally, TFB-EV treatment was associated with a coordinated repair response characterized by attenuation of inflammatory and oxidative stress responses during the early repair stage and enhancement of regenerative responses during tissue remodeling. These antioxidant responses were consistent with Nrf2-associated cytoprotective signaling, while inflammatory modulation was associated with suppression of IL-17/TNF-associated pathways. Transcriptomic analysis revealed enrichment of PI3K-Akt-associated signaling pathways, together with regenerative phenotypes including relief of G0/G1 cell cycle arrest and enhanced proliferation, migration, and angiogenesis activity of relevant cellular models. Combined with the practical advantages of liquid fermentation, TFB-EVs represent a promising fungal-derived bioactive nanotherapeutic platform with potential for future translational development. This work provides a cross-kingdom therapeutic strategy for wound repair and highlights the potential of scalable biomanufacturing approaches for future EV-based therapies.