Rejuvenating senescent hair follicles: a novel conjugated linoleic acid based nanovesicle approach to treat androgenic alopecia

Existing therapies for androgenetic alopecia (AGA) fall short of expectations due to the complex pathogenesis, deficient drug enrichment, and obvious adverse effects. Although elevated dihydrotestosterone (DHT) is responsible for the miniaturization of hair follicles (HFs), cell aging has been found to be closely associated with AGA, however not received sufficient attention before. In this study, we first explored the deleterious effects of DHT on HFs, then identified the anti-aging potential of conjugated linoleic acid (CLA) from several polyunsaturated fatty acids. We then developed CLA-loaded nanovesicles (Arg-CLAVs) capable of counteracting DHT-induced HF aging. Arg-CLAVs rejuvenated DHT-induced senescent cells by alleviating oxidative stress, reducing the production of senescence-associated secretory phenotype, and modulating the MAPK-ERK signaling pathway. Moreover, Arg-CLAVs enhanced the HF niche by facilitating angiogenesis, preserving local oxidative homeostasis, and promoting the proliferation and migration of dermal papilla cells. Given its unique properties of nanocarriers, Arg-CLAVs exhibited better skin retention and HF targeting ability compared to the normal tincture. Subsequently, minoxidil (MNX) was loaded into the nanovesicle (MNX@Arg-CLAVs) and evaluated for its hair growth-promoting efficacy in vivo. Our results demonstrated that, in both male and female AGA mice, MNX@Arg-CLAVs with reduced MNX dosage and lower organic solvent contents, exhibited stronger effects on hair regeneration promotion and anti-aging in HFs, while inducing less formulation-associated skin irritation than commercial topical MNX tincture. In sum, this study developed a novel nanoplatform with HF anti-aging activity for AGA that enables synergistic effects with existing drugs.