Dihydromyricetin-loaded TPGS/gelatin grafted-β-Cyclodextrin/ chitosan grafted-β-Cyclodextrin nano-delivery system for improving oral absorption.

Dihydromyricetin (DMY), the main functional component of vine tea, exhibits multiple biological activities and is widely used in food applications such as dairy products, functional foods, and food additives. However, its poor stability and bioavailability limit its broader utilization. To address this, CCGT-DMY-NPs were successfully prepared using chitosan-grafted-β-cyclodextrin (CS-CD), gelatin-grafted-β-cyclodextrin (Gel-CD), and vitamin E polyethylene glycol succinate (TPGS). The CCGT-DMY-NPs exhibited a particle size of 216.33 ± 7.23 nm, a polydispersity index of 0.207 ± 0.011, a zeta potential of 25.67 ± 4.53 mV, and an encapsulation efficiency of 98.21 ± 2.44 %, with significantly improved stability compared to free DMY. In vitro cellular uptake studies using confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) confirmed enhanced uptake of CCGT-DMY-NPs in Caco-2 cells. In vitro unidirectional intestinal perfusion demonstrated that CCGT-DMY-NPs significantly increased the apparent permeability coefficient (Papp) and absorption rate constant (Ka) across duodenal, jejunal, and ileal segments (p < 0.01), with jejunal Papp reaching 2.47 ± 0.59 × 10-2 cm/min compared to 0.26 ± 0.06 × 10-2 cm/min for free DMY. Mechanism studies indicated that the enhanced absorption was attributed to mucoadhesion, tight junction opening, and involvement of multiple endocytic pathways (clathrin-, caveolin-, non-caveolin-, and non-clathrin-mediated) and macropinocytosis. Pharmacokinetic studies confirmed that the area under the curve (AUC0-t) of CCGT-DMY-NPs was 2.20 times higher than that of oral DMY, and the relative bioavailability (Frel) of CCGT-DMY-NPs reached 219.89 %. These findings suggest that CCGT-DMY-NPs significantly enhance the oral bioavailability of DMY through multi-mechanistic promotion of intestinal absorption, providing a promising strategy for its application in functional foods.