Gallic acid-driven core-shell nanovehicles enable intestinal adhesion and adipose retention for enhanced oral bioavailability of cholecalciferol

-cyclodextrin (βCD) to form a stable βCD/VDC inclusion complex, improving solubility and physicochemical stability, and then coated with gallic acid (GA) to yield the core-shell nanovehicle GA/βCD/VDC-NPS, which leverages GA's intestinal mucoadhesive and mesenteric adipose retention. GA/βCD/VDC-NPS exhibited a particle size of 234.1 ± 5.23 nm, high encapsulation efficiency (81.2 ± 0.13%), and drug-loading capacity (20.10 ± 0.50%), and showed sustained release, with a cumulative release of 86.06 ± 2.35% at 72 h. MDCK (Madin-Darby Canine Kidney cells) cell experiments showed its cellular uptake was significantly higher than βCD/VDC or free VDC, mediated by multiple endocytic mechanisms. Pharmacokinetic analysis supported markedly enhanced oral absorption: relative to free VDC, the bioavailability of GA/βCD/VDC-NPS increased 2.87-fold in plasma, 6.75-fold in the small intestine, 3.40-fold in adipose tissue, and 3.50-fold in the stomach. Tissue distribution studies verified its enhanced accumulation and prolonged retention in intestinal regions and associated adipose depots. These findings highlight polyphenols like GA as bioactive shells that enhance intestinal adhesion and regional retention, improving oral hydrophobic drugs' pharmacokinetics. In conclusion, GA/βCD/VDC-NPS is a promising nanoplatform that resolves VDC's solubility and bioavailability issues via polyphenol-mediated surface functionalization, offering great potential for oral delivery of various hydrophobic active compounds.