Diabetes mellitus (DM) remains a great challenge in treatment due to pathological complexity.It has been proven that phytomedicines and natural medicines have prominent antidiabetic effects.This work aimed to develop selenium-layered nanoparticles (SeNPs) for oral delivery of mulberry leaf and Pueraria Lobata extracts (MPE),a group of phytomedicines with significant hypoglycemic activities,to achieve a synergic antidiabetic effect.MPE-loaded SeNPs (MPE-SeNPs) were prepared through a solvent diffusion/in situ reduction technique and characterized by particle size,ξ potential,morphology,entrapment efficiency (EE) and drug loading (DL).The resulting MPE-SeNPs were 120nm around in particle size with EE of 89.38％ for rutin and 90.59％ for puerarin,two marker components in MPE.MPESeNPs exhibited a slow drug release and good physiological stability in the simulated digestive fluid.After oral administration,MPE-SeNPs produced significant hypoglycemic effects both in the normal and diabetic rats.Ex vivo intestinal imaging and cellular examinations demonstrated that MPE-SeNPs were provided with outstanding intestinal permeability and transepithelial transport aptness.It was also revealed that MPE-SeNPs could alleviate the oxidative stress,improve the pancreatic function,and promote the glucose utilization by adipocytes.Our study provides new insight into the use of integrative nanomedicine containing phytomedicines and selenium for DM treatment.