Hyaluronic‐Acid‐Coated Chitosan Nanoparticles for Insulin Oral Delivery: Fabrication, Characterization, and Hypoglycemic Ability

Abstract Oral administration of insulin faces multiple biological challenges, such as varied digestive environments, mucin exclusion, and low epithelial cells’ absorption. In the present study, a hyaluronic acid (HA)‐coated chitosan (CS) nanoparticle (HCP) delivery system is fabricated for insulin oral delivery. It is hypothesized that the developed nanoparticles will protect insulin from digestive degradation, promote intestinal epithelial cell absorption, and exert strong in vivo hyperglycemic ability. Nanoparticles formulated by CS and sodium tripolyphosphate (TPP) are optimized to form the core nanoparticles (CNPs). HA is further applied to coat CNP (HCP) to improve stability, reduce enzymatic degradation, and promote absorption of insulin. HCP promotes insulin uptake by Caco‐2 cells, absorbs less mucin, and improves intestinal absorption. Moreover, an in vivo test demonstrates that oral administration of insulin‐loaded HCP exerts strong and continuous hyperthermia effect (with a pharmacological availability (PA) of 13.8%). In summary, HCP is a promising delivery platform for insulin oral administration in terms of protecting insulin during digestion, facilitating its absorption and ultimately promoting its oral bioavailability.