Chunli Qi,1– 3,* Huijie Xing,2,3,* Ning Ding,4 Weifeng Feng,5 Yongyi Wu,6 Xingwang Zhang,7 Yigang Yu1 1School of Food Science and Engineering, South China University of Technology, Guangzhou, 510641, People’s Republic of China; 2Institute of Laboratory Animals, Jinan University, Guangzhou, 510632, People’s Republic of China; 3Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, 510632, People’s Republic of China; 4Department of Animal, Plant and Food, Guangzhou Customs Technology Center, Guangzhou, 510623, People’s Republic of China; 5Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 6Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China; 7Department of Pharmaceutics, School of Pharmacy, Jinan University, Guangzhou, 511443, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xingwang Zhang, Email zhangxw@jnu.edu.cn; Yigang Yu, Email yuyigang@scut.edu.cnPurpose: Diabetes mellitus (DM) remains a significant health challenge, with traditional treatments often failing to provide lasting solutions. Taxifolin (Tax), a potential phytomedicine with antioxidant and anti-hyperglycemic properties, suffers from low water solubility and poor bioavailability, necessitating advanced delivery systems. This study aims to nanometerize taxifolin (Tax) into selenized liposomes (Tax-Se@LPs) for enhanced oral delivery and hypoglycemic effect.Methods: Tax-Se@LPs were fabricated through a thin-film hydration/in situ reduction technique. The resulting nanomedicine was characterized through in vitro release studies, pharmacokinetic and pharmacodynamic evaluations, cellular uptake assays, and formulation stability tests.Results: The optimized Tax-Se@LPs demonstrated an average particle size of 185.3 nm and an entrapment efficiency of 95.25% after optimization. In vitro release studies revealed that Tax-Se@LPs exhibited a slower and more sustained release profile compared to conventional liposomes, favoring gastrointestinal drug absorption. Pharmacokinetic evaluations in normal rats indicated that Tax-Se@LPs achieved a relative bioavailability of 216.65%, significantly higher than Tax suspensions and unmodified liposomes. Furthermore, in diabetic GK rats, Tax-Se@LPs resulted in a maximal blood glucose reduction of 46.8% and exhibited a more sustained therapeutic duration compared to other formulations. Cellular uptake tests manifested that selenization altered the internalization mechanisms of liposomes while preserving their absorption aptness by intestinal epithelial cells. The physiological and in vitro stability of Tax-Se@LPs was also reinforced by selenization.Conclusion: Overall, Tax-Se@LPs not only improve the oral bioavailability of Tax but also enhance its therapeutic efficacy. These findings underscore the potential of Tax-Se@LPs as a promising therapeutic strategy for DM management.Keywords: taxifolin, liposomes, selenium, diabetes mellitus, bioavailability, hypoglycemic effect