Nanoliposomal Co-Delivery of AR-PROTAC and NFKBIZ siRNA for Synergistic Therapy of Androgenetic Alopecia.

Androgenetic alopecia (AGA), a prevalent form of hair loss primarily affecting younger individuals, remains a significant therapeutic challenge due to the lack of effective treatments. The pathogenesis of AGA is driven by the interaction between androgen receptors (AR) and androgens, as well as by dysregulation of the follicular ecological niche resulting from excessive reactive oxygen species (ROS) and insufficient vascularization in the perifollicular microenvironment. Given the multifactorial nature of AGA, a multi-target therapeutic strategy, rather than a single-target approach, has emerged as a promising method to enhance treatment efficacy. In this study, we developed nanoliposomes (NLPs) formulation by self-assembling AR-PROTAC (ARV110) and NFKBIZ siRNA (siNFKBIZ) into nanoparticles, followed by surface modification with liposomes. This design simultaneously targets AR degradation and alleviates oxidative stress, thereby improving the follicular microenvironment and promoting hair regrowth. The NLPs formulation effectively addresses the challenge of delivering payloads to keratinocytes (HaCaT), facilitates efficient skin penetration, scavenges excess ROS, and inhibits the inflammatory response in hair follicles. Additionally, NLPs downregulate AR protein expression to modulate hair growth-associated signaling pathways, achieving a multimodal synergistic therapeutic effect for AGA. Our design offers an effective multi-target strategy for AGA, resulting in enhanced therapeutic effects for hair loss treatment.