Transdermal L-arginine and hyaluronic acid delivery to treat androgenetic alopecia through dual hormone modulation and anti-inflammatory action

L -Arginine ( L -Arg), a precursor of nitric oxide (NO), is efficiently delivered to the deeper layers of the skin via a hyaluronic acid-based liposomal transdermal delivery system (HL@ L -Arg), which enhanced cutaneous delivery and local retention of L -Arg. Through nitric oxide synthase (NOS)-mediated conversion, HL@ L -Arg promoted endogenous NO production and provided a sustained NO-related therapeutic effect. • Transcriptomic analysis indicated that HL@ L -Arg treatment in androgenetic alopecia (AGA) was associated with pathways related to Wnt signaling, inflammatory responses, and steroid hormone biosynthesis. Functional studies further showed that HL@ L -Arg reduced SRD5A1/5α-reductase activity and DHT production, while promoting β-catenin/IGF-1-associated follicular growth responses. • HL@ L -Arg improved the follicular microenvironment by suppressing inflammatory factors (TNF-α and IL-6) and androgen receptor (AR) expression, while enhancing Ki67 and VEGF expression, endothelial responses, and local blood perfusion, thereby promoting hair regeneration. Androgenetic alopecia (AGA) is a common hair loss disorder caused by genetic susceptibility and androgen-driven follicular miniaturization. Current FDA-approved therapies, including finasteride and minoxidil, are limited by adverse effects. Here, we developed a hyaluronic acid-based liposomal transdermal delivery system loaded with L -arginine (HL@ L -Arg) to enhance cutaneous delivery and promote endogenous nitric oxide (NO) production through nitric oxide synthase. Transcriptomic analysis indicated significant changes in pathways related to inflammatory responses, Wnt signaling, and steroid hormone biosynthesis. Mechanistically, HL@ L -Arg inhibited 5α-reductase activity and reduced dihydrotestosterone (DHT) production while promoting endogenous NO generation. In an AGA mouse model, HL@ L -Arg reduced TNF-α, IL-6, and androgen receptor (AR) expression, increased VEGF and Ki67 levels, and markedly promoted hair regeneration. Collectively, transdermal L -Arg delivery represents a promising endogenous NO-based therapeutic strategy for AGA through DHT suppression, regulation of the follicular microenvironment, and anti-inflammatory activity.