Abstract: AimTo study chitosan-coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) on enhancing gastrointestinal absorption of insulin. MethodsInsulin-loaded PLGA multiple emulsions were prepared by a double-emulsion method. Using chitosan as a stabilizer, chitosan-coated PLGA-NPs was prepared. The changes of the morphology, size distribution and Zeta potential of the NPs were examined. The encapsulation efficiency was determined by HPLC. The release behaviors in vitro were assessed, and the hypoglycemic effects were evaluated by monitoring the glucose levels in diabetic rats. ResultsChitosan-coated PLGA-NPs showed a narrow size of distribution and regular surface with layer structure and their Zeta potential can be changed by chitosan. Chitosan-coating increased the encapsulation efficiency of insulin, reduced the initial burst and improved the release behavior of the NPs. About 14-16 h after intragastric administration of chitosan-coated INS-PLGA-NPs, the plasma glucose level decreased significantly compared with intragastric administration of same dose of non-coated NPs (P＜0.05), and the relative pharmacological availability was increased up to (15.4±1.2)%. ConclusionChitosan-coated PLGA-NPs could enhance gastrointestinal absorption of insulin.