Enhanced Oral Delivery of Protein Drugs Using Zwitterion-Functionalized Nanoparticles to Overcome both the Diffusion and Absorption Barriers.

Oral delivery of protein drugs based on nanoparticulate delivery system requires permeation of the nanoparticles through the mucus layer and subsequent absorption via epithelial cells. However, overcoming these two barriers requires very different or even contradictory surface properties of the nanocarriers, which greatly limits the oral bioavailability of macromolecular drugs. Here we report a simple zwitterions-based nanoparticle (NP) delivery platform, which showed a great potency in simultaneously overcoming both the mucus and epithelium barriers. The dense and hydrophilic coating of zwitterions endows the NPs with excellent mucus penetrating ability. Moreover, the zwitterions-based NPs also possessed excellent affinity with epithelial cells, which significantly improved (4.5-fold) the cellular uptake of DLPC NPs, compared to PEGylated NPs. Our results also indicated that this affinity was due to the interaction between zwitterions and the cell surface transporter PEPT1. Moreover, the developed NPs loaded with insulin could induce a prominent hypoglycemic response in diabetic rats following oral administration. These results suggest that zwitterions-based NPs might provide a new perspective for oral delivery of protein therapeutics.