Lymphatic remodeling and metabolic rescue by VEGFR-3/DHA-coordinated microneedles for hair regeneration

Androgenetic alopecia (AGA) is characterized by progressive follicle miniaturization, excessive inflammation and hair follicle stem cell (HFSC) quiescence. To address these multifactorial challenges, we developed a dissolvable γ-polyglutamic acid (γ-PGA) hydrogel microneedle system (VI@MSN/MNs-DHA) delivering: (1) VEGFR-3 inhibitor (VI) encapsulated in mesoporous silica nanoparticles (MSNs) to remodel lymphatic vessel endothelial hyaluronan receptor 1-positive (LYVE1+) lymphatic networks and thereby reduce anatomical constraints on anagen entry, and (2) docosahexaenoic acid (DHA) to normalize lipid metabolism and oxidative stress. <em>In vitro</em>, VI@MSN/MN-DHA extracts demonstrated multiple bioactivities, including the suppression of lymphatic endothelial tube formation, scavenging of reactive oxygen species, and protection of HFSCs from testosterone-induced injury. <em>In vivo</em>, topical application of VI@MSN/MN-DHA in an AGA mouse model accelerated anagen onset and increased hair regrowth density by 1.37-fold compared to the untreated group. Mechanistically, it is identified that the treatment of VI@MSN/MN-DHA led to the coordinated upregulation of SOX9 and Ki67 in HFSCs, along with restoration of peroxisome proliferator-activated receptor-γ signaling. This study presents a novel strategy that combines lymphatic remodeling and metabolic reprogramming to effectively reactivate HFSCs and promote hair regeneration. The minimally invasive microneedle platform offers a novel microenvironment-engineering paradigm for safe and effective AGA therapy.