HDAC1-overexpressing dermal papilla cell-derived extracellular vesicles modulate p53 and Wnt/β-catenin signaling to rescue hair follicle regeneration in androgenetic alopecia.

Androgenetic alopecia (AGA), a prevalent non-scarring alopecia, poses significant therapeutic limitations due to the restricted efficacy and potential side effects of current interventions. Cell-derived nanovesicles (CNVs), noted for their biocompatibility and efficient delivery capacity, have been investigated as promising therapeutic carriers. Comparative studies of CNVs sourced from HaCat cells, adipose-derived stem cells, and dermal papilla cells demonstrated that those derived from dermal papilla cells exhibit enhanced cellular internalization and targeting specificity. Proteomic analyses revealed a notable suppression of Histone Deacetylase 1 (HDAC1) expression in balding scalp regions of AGA patients, suggesting involvement in cell cycle dysregulation and senescence-related processes. HDAC1-overexpressing nanovesicles were subsequently developed, characterized by high encapsulation efficiency, favorable biomimetic profiles, and cost-effective scalability. These engineered nanovesicles substantially improved cellular proliferation and migration capacities while mitigating dihydrotestosterone (DHT)-induced cytotoxicity. Transcriptomic evaluations suggested their role in promoting hair follicle regeneration via modulation of p53 and Wnt/β-Catenin signaling pathways. To address limitations in intradermal delivery, a dissolvable microneedle platform was constructed to enable precise, sustained release with excellent biocompatibility and targeted administration. Therapeutic efficacy was validated through comprehensive in vitro assays and in vivo models, supporting the translational potential of this cell-free nanotherapeutic strategy in AGA management.