Glucose-Responsive Polyzwitterionic Nanoparticles with Enhanced and Targeted Intestinal Epithelial Absorption for Oral Insulin Delivery.

Oral administration of insulin for diabetes mellitus treatment has always been challenging due to a series of physiological barriers in the gastrointestinal tract. Herein, we developed glucose-responsive polyzwitterionic nanoparticles (NPs) for oral delivery of insulin, which were loaded into enteric capsules to overcome the barriers in the stomach. Glucose could bind with phenylboronic acid (PBA) of NPs to increase their negative charge density, thereby achieving glucose-responsive insulin release in a hyperglycemic environment. It was proven that NPs with polyzwitterionic poly[2-(methacryloyloxy)ethyl choline phosphate] (PMCP) could overcome the mucus barrier. In particular, polyzwitterionic PMCP could promote the NPs across the epithelial cell layer, which was attributed to the targeting and specific CP-PC interaction between polyzwitterionic PMCP and the epithelial cell membrane. The NPs in enteric capsules could significantly enhance the oral bioavailability of insulin to 14.2% in streptozotocin-induced type 1 diabetic mice, which resulted in a good hypoglycemic effect after single or continuous oral administration. Importantly, the NPs in enteric capsules did not induce any observable increase in terms of pro-inflammatory cytokines or pathological change of the small intestines. Therefore, this work provides a promising insulin oral delivery system for the safe and efficient treatment of diabetes mellitus.