Spermine Lipid Assembled Nanoparticles for siRNA Delivery and Androgenetic Alopecia Therapy

Androgenetic alopecia (AGA) is characterized by progressive hair loss caused by abnormal androgen levels in hair follicles, which has a substantial impact on both the physiological and psychological well-being of patients. The androgen receptor (AR) has been validated as an important target, and the local application of AR-targeting small-interference RNAs (siRNA) has been identified as a promising treatment for AGA. Nevertheless, the clinical utilization of RNAi therapy has been hampered by inefficient delivery, potential inflammatory responses, and poor in vivo retention capacity. Here, a series of spermine-derived ionizable lipids with varying alkyl chains (Sper- N, N = 8, 12, 16) were synthesized and subsequently coformulated with DSPC and a PEG-lipid to generate Sper- N /siRNA lipid nanoparticles. In vitro studies have demonstrated that Sper-12-based nanoparticles facilitate efficient siRNA delivery for AR gene silencing as well as the internalization of ASOs and plasmid DNA. Further in vivo studies with intradermal administration of Sper-12/siAR nanoparticles have confirmed effective suppression of aberrant AR protein in androgenetic alopecia model mice, promotion of hair follicle proliferation, and alleviation of hair loss symptoms. The Sper-12/siRNA nanoparticles provide a versatile delivery platform to advance siRNA-based therapeutics for androgenetic alopecia.