Fisetin topical delivery via ascorbyl palmitate/hyaluronan-enhanced limosomes: a novel paradigm for preventing UVB-induced skin photoaging

This study investigates the topical delivery of Fisetin (FIS) to counteract UVB-induced skin photoaging. Due to FIS's poor solubility and high lipophilicity, it was encapsulated in D-limonene-modified phospholipid carriers, limosomes (LIMOs), co-formulated with Ascorbyl Palmitate (AP) and Hyaluronan (HYA) to improve FIS's solubility, skin penetration, and photoprotective efficacy. FIS-AP-HYA-LIMOs exhibited small size (81.50 ± 0.98 nm), high entrapment (98.93 ± 0.13%), and sustained release over 24 h. FT-IR and DSC confirmed the successful formation of FIS-AP-HYA-LIMOs. The <i>ex vivo</i> permeation study showed high flux (10.54 ± 0.40 µg.cm^-2.h^-1), reflecting evident skin penetration. Confocal microscopy proved the ability of FIS-AP-HYA-LIMOs to deposit FIS to a skin depth of 128 µm with a strong FIS fluorescence in skin layers. FIS-AP-HYA-LIMOs showed potent <i>in vitro</i> antioxidant activity, high biocompatibility, and remained stable for 6 months. <i>In vivo</i> studies revealed the downregulation of MMP9, TNFα, and NF-κB, accompanied by increased SOD and CAT levels, indicating superior anti-ageing, anti-inflammatory, and antioxidant effects compared to FIS suspension. FIS-AP-HYA-LIMOs decreased JNK expression, preserved the integrity of skin layers, and reduced collagen degradation. This is the first report on FIS-loaded limosomes, modified with AP and HYA to synergistically prevent UVB-induced photoaging.