Coordinated Regulation of Signaling Pathways by Stem Cell-Derived Extracellular Vesicles: A Promising Strategy Against Skin Photoaging.

Ultraviolet (UV) radiation accelerates skin aging by promoting collagen breakdown, inflammation, and oxidative stress. Recent studies have identified stem cell-derived extracellular vesicles (EVs) as promising agents for treating photoaging due to their ability to carry bioactive molecules, including microRNAs, cytokines, and growth factors. These EVs mitigate UV-induced skin damage by modulating multiple signaling pathways, such as TGF-β/Smad, MAPK/AP-1, NF-κB, and SIRT1, resulting in decreased matrix metalloproteinase (MMPs) activity, reduced inflammatory cytokines, and enhanced collagen synthesis. Nevertheless, the therapeutic effects of EVs vary depending on their stem cell source, each exhibiting distinct biomolecular profiles and specific pathway interactions. Current evidence is mainly derived from in vitro or subcutaneous administration models; the feasibility of topical delivery which is more practical for clinical application remains to be determined due to skin barrier penetration challenges. Despite their potential, significant challenges remain, including diverse EV compositions, the absence of standardized isolation protocols and difficulties in large-scale production. Addressing these issues through targeted mechanistic research and optimized delivery strategies will facilitate the development of precise and effective EVs-based therapies for skin photoaging. Compared with existing reviews, we systematically summarize the crosstalk among multiple photoaging-related signaling pathways and the source-dependent functional heterogeneity of stem cell-derived EVs.