Platycladus orientalis Leaf-Derived Exosome-like Nanovesicles Delivered by Hydrogel Microneedles Restore Follicular Immune Homeostasis and Promote Hair Regeneration in Androgenetic Alopecia

Abstract

Androgenetic alopecia (AGA) is the most prevalent form of hair loss, yet current therapies offer limited efficacy and fail to restore the disrupted follicular immune microenvironment. Here, we developed a bioactive hydrogel microneedle system (P-MN) in which Platycladus orientalis leaf-derived exosome-like nanovesicles (Plao-ELNs) were encapsulated within a methacrylated hyaluronic acid/cactus polysaccharide (HAMA/CP) matrix for transdermal AGA therapy. The HAMA/CP hydrogel was evaluated for biocompatibility, antibacterial activity, and effects on the migration of dermal papilla cells (DPCs) in vitro; P-MN was assessed for hair regrowth, follicular architecture, and anagen induction in a murine AGA model; and the underlying mechanisms were examined using transcriptomics, flow cytometry, and molecular assays. The HAMA/CP hydrogel showed good biocompatibility and antibacterial activity, and enhanced the migration of DPCs, while enabling sustained intradermal retention of Plao-ELNs. In vivo, P-MN accelerated hair regrowth, restored follicular architecture, and increased the proportion of hair follicles in the anagen phase. Mechanistically, Plao-ELNs suppressed aberrant T-cell activation and reduced IL-17A secretion, thereby inhibiting NF-κB-mediated DKK1 expression and reactivating Wnt/β-catenin signaling in DPCs to promote hair follicle regeneration. The HAMA/CP matrix potentiated efficacy through antibacterial protection and prolonged local delivery, supporting P-MN as a promising strategy for AGA treatment.