Transdermal Delivery of Valproate–Choline Ionic Liquid Induces Hair Regrowth

Alopecia treatment research has been increasingly focused on innovative materials systems and drug delivery methods. Valproic acid (VPA) has been shown to promote hair regrowth by upregulating the Wnt/β-catenin signaling pathway, a key regulator of hair papilla cell proliferation. However, topical administration of VPA typically requires organic solvents or complex transdermal devices to enhance skin penetration. Biocompatible ionic liquids have gained attention as customizable solvents for transdermal drug delivery (TDD). In this study, we introduce a novel choline-based valproic acid ionic liquid (VPA-IL) for the treatment of hair loss. Our findings demonstrate that VPA-IL significantly enhances the transdermal penetration of VPA by disrupting the lipid bilayer structure of stratum corneum (SC), due to strong hydrogen bonding between the methyl hydrogen of the choline and the carboxyl group of phospholipid molecules. In vivo pharmacodynamic assessments revealed that topical application of VPA-IL effectively promotes hair regrowth by activating the Wnt/β-catenin pathway and upregulating proliferating cell nuclear antigen (PCNA), K14, loricrin, and several hair follicle (HF) stem cell markers without causing skin irritation or systemic toxicity. This work offers a safe and promising new therapeutic option for alopecia.