Oral delivery of insulin is of great convenience in treating diabetes but is still subject to the harsh gastrointestinal tract. Herein, we developed an intelligent oral insulin platform based on glucose-responsive polymeric nanoparticles (NPs), which possess the following advantages: (1) protect the integrity and bioavailability of loaded insulin against gastrointestinal tract, (2) overcome the intestinal epithelial barriers via neonatal Fc receptor-mediated transport, and (3) on-demand release of insulin dependent solely on blood glucose levels to avoid hyperglycemia and hypoglycemia caused by unsafe doses of insulin. Notably, our oral NPs extended the therapeutic effect to up to 16 h in type 1 diabetic mice. To our knowledge, this is the longest effective time among such types of oral insulin platforms reported to date and may reduce the frequency of insulin administration to once daily. This platform might be useful for the oral delivery of biologics in treating diabetes and related complications.