Injectable polysaccharide-based hydrogel delivering Poria cocos extracellular vesicles promotes hair regeneration in androgenetic alopecia via Wnt/β-catenin signaling

Androgenetic alopecia (AGA) is characterized by progressive hair follicle miniaturization driven by premature follicle regression. While extracellular vesicles (EVs) are potent bioactive therapeutics, their clinical translation is hindered by the low yields and poor stability of mammalian-derived sources. Herein, we developed an injectable biomacromolecular hydrogel composed of sodium carboxymethylcellulose (CMCNa), sodium alginate (SA), and hyaluronic acid (HA) to deliver plant-derived Poria cocos extracellular vesicles (PCEVs) for the topical treatment of AGA. This polysaccharide matrix was engineered to localize vesicular cargo within the follicular niche, preserve vesicle integrity, and facilitate the sustained release of PCEVs. The hydrogel exhibited favorable rheological properties, injectability, and cytocompatibility for topical application. In a dihydrotestosterone (DHT)-induced AGA mouse model, topical administration of the PCEV-loaded hydrogel significantly accelerated hair regrowth, enhanced follicle density, and restored hair bulb volume and dermal thickness. Transcriptomic profiling revealed that the therapeutic effect was driven by Wnt/β-catenin signaling activation. Specifically, PCEVs treatment led to the upregulation of differentiation markers homeobox C13 (Hoxc13) and forkhead box N1 (Foxn1), hair-shaft keratin Krt31, and desmoglein 4 (Dsg4), along with the downregulation of stem-cell quiescence markers nuclear factor of activated T cells 1 (Nfatc1) and Cd34. Collectively, this delivery platform effectively leverages plant-derived EV cargo to reverse stem-cell quiescence and promote follicular regeneration, offering a scalable and stable translational strategy for hair loss disorders.