Synergistic Tissue Remodeling by Stem Cell-Derived Extracellular Vesicles and Nanofiber-Hydrogel Composite Ameliorates Radiation Dermatitis.

Radiation dermatitis (RD) is a debilitating side effect of radiation therapy, affecting nearly 95% of irradiated cancer patients, yet no FDA-approved therapies exist. Here, we introduce a nanofiber-hydrogel composite (NHC) matrix loaded with adipose-derived stem cell extracellular vesicles (ADSC-EVs), enabling sustained host cell recruitment and EV release in vivo. A single subcutaneous injection following ionizing radiation prevents functional and histological sequelae of radiation damage, whereas bolus EVs or NHC alone do not. Treated skin regenerates near-normal epidermal and dermal architecture with preservation of dermal appendages. Mechanistically, NHC modulates local inflammation by promoting pro-regenerative macrophage polarization and reducing pro-fibrotic fibroblast differentiation, while sustained EV delivery enhances angiogenesis, hair follicle regrowth, and neo-follicle formation. Pathway analysis indicates that NHC primarily modulates IL-17-associated inflammatory signaling, whereas EVs activate Relaxin and PI3K-Akt pathways linked to tissue regeneration. Together, NHC and EVs synergistically remodel irradiated tissue and represent a practical, off-the-shelf therapeutic strategy for RD.