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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\u2013shell nanoparticles with thiolated hyaluronic acid (HA\u2010SH) coating (NP<jats:sub>HA\u2010SH<\/jats:sub>) are produced utilizing a two\u2010step flash nanocomplexation process to enhance oral delivery efficiency of insulin. A positively charged nanoparticle core is first generated by electrostatic complexation between insulin and <jats:italic>N<\/jats:italic>\u2010(2\u2010hydroxypropyl)\u20103\u2010trimethyl ammonium chloride modified chitosan (HTCC), followed by surface coating with HA\u2010SH. The optimized NP<jats:sub>HA\u2010SH<\/jats:sub> 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 NP<jats:sub>HA\u2010SH<\/jats:sub> shows high mucus\u2010penetration ability, improved intestinal retention and transepithelial transport property due to its thiolated surface and the ability of HA\u2010SH coating to dissociate from the nanoparticle surface when across the mucosal layer. Oral administration of NP<jats:sub>HA\u2010SH<\/jats:sub> to Type 1 diabetic rats yields high efficacy and an average relative bioavailability of 11.3%. These results demonstrate that the HA\u2010SH coated core\u2013shell nanoparticles are a promising oral delivery vehicle for protein therapeutics.<\/jats:p>","DOI":"10.1002\/adhm.201800285","type":"journal-article","created":{"date-parts":[[2018,7,9]],"date-time":"2018-07-09T02:01:16Z","timestamp":1531101676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":128,"title":["Uniform Core\u2013Shell Nanoparticles with Thiolated Hyaluronic Acid Coating to Enhance Oral Delivery of Insulin"],"prefix":"10.1002","volume":"7","author":[{"given":"Houkuan","family":"Tian","sequence":"first","affiliation":[{"name":"School of Materials Science and Engineering Center for Functional Biomaterials Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education Sun Yat\u2010sen University  Guangzhou 510275 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