Here we report the development of polymeric nanoparticles, made of poly(lactide-co-glycolide) (PLGA) chemically modified with mannosamine (MN), intended to specifically interact with the intestinal mucosa and facilitate the intestinal transport of proteins. PLGA-MN nanoparticles displayed nanometric size and a negative zeta potential, which was lower than that of the PLGA nanoparticles. This correlate well with the preferential location of the MN group on the nanoparticles surface obtained by X-ray photoelectron spectroscope (XPS). The presence of MN groups in the polymer chain led to a different surface morphology noted by SEM, an increase of the encapsulation of model proteins, and to help stabilizing the nanoparticles in simulated intestinal fluids. Furthermore, the MN modification significantly enhanced the nanoparticle's interaction with the epithelial cells in human intestinal follicle-associated epithelium cell culture model. Overall, the MN modification significantly modifies the properties of PLGA nanoparticles making them more suitable as nanocarriers for oral protein delivery.