Oral delivery of protein and peptide drugs presents considerable challenges due to their susceptibility to digestive enzymes in gastrointestinal (GI) tract and low efficiency of transepithelial transport. Herein, inspired by efficient absorption of protein-based nutrients, we constructed several kinds of oral drug delivery systems by mimicking natural amino acid and oligopeptide absorption route. Three kinds of amino acids and two kinds of oligopeptides were chosen as targeting ligands to mediate transportation of orally administered nanoparticles (NPs). Liraglutide (Lira), a kind of glucagon like peptide-1 (GLP-1) receptor agonist, was used as model drug. These functionalized NPs could protect Lira from enzymatic degradation in GI tract. Moreover, compared with amino acid-modified NPs, oligopeptide-modified NPs exhibited greater transepithelial transport efficiency and were primarily absorbed in the proximal small intestine due to the high expression and transportation mediated by proton coupled oligopeptide transporter 1 (PEPT1). These Lira-loaded NPs could effectively control the blood glucose level, reduce plasma lipid level, and repair tissue damage on type 2 diabetic mice and even showed comparable hypoglycemic effects of subcutaneous injection (s.c.) free Lira. Our study demonstrates the potential of mimicking natural oligopeptide absorption route to enhance oral delivery of protein and peptide drugs.