Multistage Transdermal Nitric Oxide Delivery System for the Efficient Treatment of Androgenic Alopecia

Androgenic alopecia (AGA) is a prevalent progressive hair loss condition. The main therapeutic drug, minoxidil, is limited by its poor efficacy and side effects such as contact dermatitis and hypertrichosis. Nitric oxide (NO), an endothelial-derived relaxing factor, promotes angiogenesis and accelerates blood flow, enhancing nutrient supply similar to minoxidil. Accordingly, we utilized a poly(vinyl alcohol) film (PVA) loaded with hyaluronic acid (HA) liposomes to construct a multistage transdermal NO delivery system (PVA@HL/NONOate) for the treatment of AGA. The HA liposomes provided efficient NO loading and extended release, while the PVA film improved skin penetration and sustained NO release, increasing NO bioavailability. Low-concentration NO effectively enhanced hair follicle vitality and repaired blood vessels. Mechanistically, low-concentration NO could treat AGA mainly by regulating the HIF-1 signaling pathway to promote angiogenesis, reducing inflammation by downregulating the expression of TNFRSF9 and IL-6, repairing hair follicles by downregulating the expression of genes in the CXCL5-IL-17 inflammatory axis.