Hydrogel microneedle delivery of a palmitoylated peptide promotes hair regeneration via dual activation of Wnt/β-catenin and cAMP–PKA signaling

Bioactive peptides are promising candidates for hair regeneration, but their topical application is often limited by poor skin delivery and the need for frequent dosing. To overcome these challenges, we designed a palmitoylated peptide, Pal-MPAPO, and incorporated it into a hyaluronic acid-based hydrogel microneedle (MN) system for localized transdermal delivery. The fabricated MNs showed adequate mechanical strength for skin insertion and provided a time-dependent, prolonged release of Pal-MPAPO. In human dermal papilla cells (DPCs), Pal-MPAPO activated the Wnt/β-catenin pathway and increased intracellular cyclic adenosine monophosphate (cAMP) levels in a predominantly VPAC1-dependent manner. Additional VPAC2 validation did not reveal a significant contribution to cAMP signaling under the tested conditions. Functional interactions between Pal-MPAPO and VPAC1 were supported by molecular docking, molecular dynamics simulations, receptor knockdown, and fluorescence imaging. In a C57BL/6 mouse model, Pal-MPAPO-loaded MNs significantly promoted hair regrowth, achieving efficacy comparable to minoxidil but at a reduced application frequency. These findings identify Pal-MPAPO as a potential peptide candidate for hair regeneration and suggest that hydrogel MN-assisted delivery provides a localized peptide administration strategy.