Follicle-Targeted Deep Eutectic Solvent-Lipid Hybrid Nanocarriers for Phloretin against Androgenetic Alopecia

Androgenetic alopecia (AGA) represents the most prevalent form of hair loss globally. Currently, minoxidil (MNX) is the only FDA-approved topical medication for AGA, but its use is limited by suboptimal efficacy and noticeable side effects. These limitations underscore an urgent demand for safer and more effective treatment options. Phloretin (PHL), a natural flavonoid, offers anti-inflammatory and antioxidant benefits that make it a promising candidate for AGA therapy. However, its practical application is restricted by poor water solubility and low skin permeability. To overcome these challenges, this study used a betaine-mandelic acid deep eutectic solvent (BMDES) to considerably improve the solubility and skin penetration of PHL. Due to the high viscosity of pure BMDES, which can compromise patient comfort, we developed a hybrid nanoparticle system, called BMDES-Lip@PHL, by combining 50% BMDES with liposomes. This strategy effectively harnesses the high drug-loading capacity of BMDES and the follicular targeting and retention properties of liposomes, thereby overcoming the limitations associated with each individual system. In vitro experiments BMDES-Lip@PHL significantly boosted the proliferation and migration of human dermal papilla cells and reduced oxidative stress. It also encouraged follicular angiogenesis and lowered the levels of pro-inflammatory factors. In AGA models, BMDES-Lip@PHL significantly stimulated hair regrowth and prevented collagen degradation induced by oxidative stress and inflammation. Furthermore, the system efficiently eliminated reactive oxygen species, suppressed the inflammatory cytokine TNF-α, reduced lipopolysaccharide-induced nitric oxide production, down-regulated interleukin-6, and promoted angiogenesis, all contributing to a healthier follicular microenvironment. Mechanistic analysis revealed that BMDES-Lip@PHL is associated with Wnt/β-catenin and mTOR signaling, alongside marked Sox9 and phosphorylated S6 up-regulation. Overall, BMDES-Lip@PHL showed outstanding safety and successfully delivered multiple functions including solubilization, penetration enhancement, retention, and targeting, indicating its strong potential as a treatment for AGA.