Black phosphorus nanosheets encapsulated microneedle for multifunctional therapy for androgenic alopecia

Androgenetic alopecia (AGA), a chronic and progressive disease, significantly impacts the patients' social, emotional, and mental well-being. Current treatment for AGA are mainly limited by drug side effects and the stratum corneum (SC) barrier of scalp. To address these issues, we developed a microneedle (MN) system loaded with black phosphorus nanosheets (BP) encapsulating baicalin (BA), a natural ingredient, for effective treatment of AGA. We first fabricated BP-BA based on the BP properties of high drug loading capacity and excellent photothermal conversion efficiency. Upon 635 nm laser irradiation, BP-BA demonstrated efficient photothermal conversion to mild thermal of ~ 42 °C. This mild thermal effect controlled BA's stimuli-responsive release, enhanced cellular uptake, and effectively modulated gene expression in dihydrotestosterone-treated human dermal papilla cells, downregulating negative regulators such as SRD5A2, AR, DKK1, and TGFB1, while upregulating positive regulators like CTNNBIP1 and VEGFA. Furthermore, we encapsulated BP-BA to MN fabricating BP-BA@MNs to overcome the SC barrier. Compared with BP-BA@MNs without laser irradiation, BP-BA@MNs with laser irradiation significantly enhanced drug penetration into the subcutaneous area and accumulation at the follicular site. Importantly, BP-BA@MNs demonstrated synergistic efficacy against testosterone-induced AGA in vivo through combining BA chemotherapy, BP-mediated mild photothermal therapy, and MN delivery, as well as good biocompatibility and biosafety, and the underlying synergistic mechanism was elucidated in terms of follicular microenvironment reconstruction. This combining BP mild photothermal and MN system is a promising approach for follicular targeted drug delivery, providing a multifunctional strategy for addressing the clinical needs of anti-AGA.