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Although oral delivery of exenatide has significant advantages, its poor permeability through intestinal epithelial membranes and rapid digestion by pepsin and ereptase in the gastrointestinal tract make effective oral delivery of exenatide a formidable challenge. In this study, we constructed a zinc ion (Zn2+) and exenatide complex functionalized nanoparticle (NP) oral delivery system to overcome the above-mentioned issue. Polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) was used as a drug carrier to escape enzymatic degradation in the gastrointestinal tract, and low molecular weight protamine (LMWP) was used as a functional group to increase penetration of NPs into the intestinal epithelium. The functionalized NPs exhibited significantly improved penetration across the intestinal epithelium, as shown by cell uptake and transmembrane transport experiments. Moreover, a significant hypoglycemic effect was observed in diabetic rats. The relative bioavailability of the orally administered functionalized NPs vs. subcutaneous injection was 7.44%, 29-fold that of the exenatide-Zn2+ solution group. These findings indicate that our modification could effectively improve exenatide treatment.