Nanoemulsion Co-delivering 4-Butylresorcinol, Undecylenoyl Phenylalanine, and Stearyl Glycyrrhetinate for Enhanced Multi-target Hyperpigmentation

Hyperpigmentation remains a significant dermatological challenge. Although 4-butylresorcinol (4-BR), undecylenoyl phenylalanine (UPA), and stearyl glycyrrhetinate (SG) exhibit complementary mechanisms targeting these pathways, their therapeutic potential is limited by poor solubility, instability, and insufficient skin permeation. To overcome these barriers, a nanostructured emulsion system co-encapsulating 4-BR, UPA, and SG (BUS-NEs) was developed via high-pressure homogenization. The optimized BUS-NEs displayed a mean particle size of 55.01 nm, encapsulation efficiencies exceeding 90%, good stability, and a sustained release profile. Compared with Free-BUS, BUS-NEs significantly improved cellular uptake and skin permeation while maintaining excellent biocompatibility. Mechanistic studies revealed that BUS-NEs exerted superior anti-melanogenic effects by potently inhibiting intracellular tyrosinase activity, reducing melanin production, and downregulating key genes in the α-MSH-stimulated signaling pathway. Furthermore, BUS-NEs displayed robust antioxidant and anti-inflammatory activities, effectively scavenging ROS and suppressing the secretion of pro-inflammatory cytokines. These multifunctional benefits were validated in advanced models: BUS-NEs significantly reduced melanin deposition and improved skin brightness in UVB-irradiated 3D reconstructed human skin, and demonstrated pronouncedc depigmentation and antioxidant protection in vivo using zebrafish models. In conclusion, the BUS-NEs platform successfully overcomes the delivery limitations of 4-BR, UPA, and SG, enabling their complementary, multi-target action for effective hyperpigmentation management, representing a promising nanotechnological strategy for advanced dermocosmetic applications. Download: Download high-res image (304KB) Download: Download full-size image