Uniform Core–Shell Nanoparticles with Thiolated Hyaluronic Acid Coating to Enhance Oral Delivery of Insulin

Oral delivery of protein drugs is an attractive route of administration due to its convenience for repeated dosing and good patient compliance. However, currently oral protein therapeutics show very low bioavailability mainly due to the existence of hostile gastrointestinal (GI) environments, including mucus layers and intestinal epithelial barriers. Herein, using insulin as a model protein therapeutic, the core–shell nanoparticles with thiolated hyaluronic acid (HA‐SH) coating (NPHA‐SH) are produced utilizing a two‐step flash nanocomplexation process to enhance oral delivery efficiency of insulin. A positively charged nanoparticle core is first generated by electrostatic complexation between insulin and N‐(2‐hydroxypropyl)‐3‐trimethyl ammonium chloride modified chitosan (HTCC), followed by surface coating with HA‐SH. The optimized NPHA‐SH shows an average size of 100 nm with high encapsulation efficiency (91.1%) and loading capacity (38%). In vitro and ex vivo results confirm that NPHA‐SH shows high mucus‐penetration ability, improved intestinal retention and transepithelial transport property due to its thiolated surface and the ability of HA‐SH coating to dissociate from the nanoparticle surface when across the mucosal layer. Oral administration of NPHA‐SH to Type 1 diabetic rats yields high efficacy and an average relative bioavailability of 11.3%. These results demonstrate that the HA‐SH coated core–shell nanoparticles are a promising oral delivery vehicle for protein therapeutics. Uniform core–shell nanoparticles with a positively charged HTCC/insulin nanocomplex core and a thiolated hyaluronic acid (HA‐SH) coating are engineered with a two‐step flash nanocomplexation (FNC) process to improve intestinal retention, mucus‐penetration ability, and transepithelial transport efficiency, thus collectively enhancing the efficacy and bioavailability of the encapsulated insulin after oral administration.