(432f) Silica Nanoparticles Act As Permeation Enhancers to Enable Oral Protein Delivery

Oral delivery of macromolecular drugs is a major unmet need in biomedicine. Poor absorption across the intestinal epithelium poses the greatest challenge to clinical translation. Here, we show that silica and other anionic nanoparticles facilitate the intestinal absorption of macromolecules, including insulin. Particles improved permeability across Caco-2 intestinal epithelial monolayers, with smaller (≤ 100 nm) and more negative particles being more effective. In mice, 50 nm silica particles enhanced the absorption of 4,000 MW dextran and insulin in a dose-dependent manner. Furthermore, oral co-administration of silica nanoparticles and insulin-loaded capsules reduced blood glucose levels in healthy mice for more than 10 hours at insulin doses as low as 10 U/kg. Nanoparticle action is due to integrin binding, which activates myosin light chain kinase and rearranges the tight junction protein, ZO-1. Together, these data suggest that inexpensive silica nanoparticles enable true oral delivery of macromolecular therapeutics by reversibly opening intestinal tight junctions and without damaging tissue.