Robust Metformin Nanosystem Promotes Hair Growth in Androgenetic Alopecia

Androgenetic alopecia (AGA)-a condition characterized by hair loss due to aging, autoimmune responses, stress, and other factors-results in hair follicle (HF) shrinkage and dermal papilla cell apoptosis. So far, only minoxidil (MXD) and finasteride have been approved for AGA treatment. However, both drugs have serious side effects, including hypersensitivity and sexual dysfunction. Hence, novel treatment agents are required for AGA. Although metformin (Met) is primarily a diabetes drug, it is also known to promote hair growth. However, it shows low transdermal permeability, and the mechanisms underlying its therapeutic effects on AGA remain unclear. Two-dimensional black phosphorus nanosheets (BP NSs) have attracted attention as drug carriers due to their low cytotoxicity, good biocompatibility, and strong antioxidant capacity. However, they are unstable, prone to degradation, and unsuitable for transdermal drug delivery. Fortunately, this limitation can be addressed through modification strategies, such as polyethylene glycol (PEG) addition (PEGylation). Here, we PEGylated BP NSs to improve their stability and loaded them with Met to generate a transdermal system (BP-PEG-Met) for AGA treatment. Compared with topical MXD, BP-PEG-Met markedly promoted hair regeneration while inducing fewer side effects. BP-PEG-Met scavenged excessive reactive oxygen species in skin cells, reducing the oxidative stress around HFs. Moreover, it up-regulated the expression of vascular endothelial growth factor (VEGF) and platelet-endothelial cell adhesion molecule-1 (CD31) in dermal papillae, inducing angiogenesis around HFs and accelerating the hair cycle toward anagen. Overall, this BP-PEG-Met transdermal delivery system showed marked clinical potential as a multifunctional tool for treating alopecia and possibly managing other skin conditions.