Transethosomes Loaded with Morin Semicarbazone and Fucoxanthin Attenuate Solar-Simulated Radiation-Induced Skin Damage in a Phenion® Full-Thickness Model

Introduction/Objectives: Prolonged exposure to solar radiation triggers oxidative stress and inflammation, accelerating skin photoaging and photocarcinogenesis. This study evaluated a novel hybrid formulation acting as a biological photoprotective adjuvant system, featuring transethosomes co-encapsulating fucoxanthin (FX) and morin semicarbazone (MS), incorporated within a hyaluronic acid (HA) hydrogel matrix. Methodology: Dual-loaded transethosomes were prepared via thin-film hydration and screened for vesicular optimization. Biocompatibility (adapted OECD TG 439) and efficacy in preventing photo-induced skin damage under simulated solar radiation (12 J/cm2) were evaluated using a 3D full-thickness human skin model (Phenion®), comparing the high-dose transethosomal hydrogel (M2) with a non-encapsulated active hydrogel (NTgel). Results: The T1 formulation (1:1 FX:MS molar ratio) demonstrated encapsulation efficiencies (>99% FX, 72.4% MS). HA hydrogel incorporation significantly enhanced 4-week active stability. The tested formulations (Tempty-in-gel and M2) were non-irritating (approximately 100% tissue viability). Under irradiation, while NTgel offered surface-level action via reduced MMP-1 levels, M2 achieved enhanced overall tissue protection, effectively suppressing inflammatory markers (COX-2, IL-6, IL-1a) and attenuating extracellular matrix degradation by decreasing MMP-9 protein levels, ultimately promoting COL1A1 restoration toward baseline levels. Conclusion: The hybrid M2 system establishes itself as a biocompatible, promising, and advanced biological photoprotective adjuvant formulation for the topical prevention of photo-induced skin damage.