Zein and Trimethyl Chitosan-Based Core–Shell Nanoparticles for Quercetin Oral Delivery to Enhance Absorption by Paracellular Pathway in Obesity Mice

Quercetin as a flavonoid polyphenol in nature has shown great anti-obesity effects. Due to its poor stability in chemical structure and low intestinal absorption, the in vivo bioavailability of quercetin is considered to be the main challenge for applications. To achieve the oral quercetin administration, chitosan was successfully trimethylated (TMC) to coat the quercetin-loaded zein nanoparticles (Zein-Q), which were designed as the core-shell structure for enhancing the intestinal absorption in this study. TMC-Zein-Q was demonstrated to protect quercetin from degradation and showed the sustained-release effect in an in vitro drug release experiment. The nanoparticles were found to reversibly open tight junctions between intestinal epithelial cells and help to increase quercetin uptake via the paracellular pathway in Caco-2 cells. In addition, the delivery system also showed stronger intestinal permeability and mucoadhesion in vivo, which improved the bioavailability of quercetin in cellular and animal experiments. After 10 weeks of intervention, TMC-Zein-Q could effectively suppress weight gain, improve serum lipid levels, and ameliorate hepatic steatosis and glucose tolerance in high-fat diet (HFD) mice by mediating the AMPK pathway. Consequently, this work successfully constructed TMC-Zein-Q for oral quercetin delivery, providing a novel and feasible strategy for the treatment of obesity via the oral route.