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

Abstract 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) Vascular endothelial growth factor receptor 3 (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. In vitro, 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. In vivo, 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 SRY-box transcription factor 9 (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.