Low-dose rapamycin microdepots promote hair regrowth via autophagy modulation

Purpose: Current therapies for hair loss, including orally administered finasteride, baricitinib, and topically applied minoxidil, are effective but have limitations related to poor patient compliance or low absorption, leading to inconsistent outcomes. This study developed injectable microdepots containing poly(lactic-co-glycolic acid) and rapamycin (RAP_MD) to address these issues. Methods: RAP_MD was fabricated using an emulsification solvent-evaporation method. The microdepots were comprehensively characterized, including their size, loading capacity, loading efficiency, and release profile. The in vitro and in vivo efficacy of RAP_MD were evaluated through gene analysis and further assays. Results: RAP_MD exhibited a spherical shape with an average size of 6 μm and a loading efficiency of approximately 71%. The in vitro release study revealed a sustained release of rapamycin, with about 70% released over 35 days, remarkably promoting hair regrowth. Importantly, in vivo results demonstrated that low-dose RAP_MD effectively induced the transition of hair follicles into the anagen phase in mice models via modulating autophagy and Wnt/β-catenin pathway. Conclusion: These findings highlight that local injection of PLGA microdepots, with their sustained drug release profile is an effective strategy for promoting hair regrowth in patients experiencing hair loss.