Propanoic acid-functionalized chitosan decorated liposomes for enhanced oral delivery and hypoglycemic effect of insulin

To enhance the oral bioavailability and hypoglycemic effect of insulin, we developed a novel bilayer liposome delivery system in this study. The outer layer of this system was decorated with propanoic acid-functionalized chitosan (CS/PA) to improve gastrointestinal stability and facilitate intestinal targeting of mono-carboxylate transporter protein 1 (MCT1). We encapsulated insulin in this newly developed delivery system. The CS/PA coating significantly enhanced the protective effect of liposomes on insulin in the gastrointestinal environment. Experiments using Caco-2 cells and ligated intestinal loops showed that IN-LIP-CS/PA facilitated insulin absorption and increased intestinal permeability. Importantly, MCT1-mediated energy-dependent endocytosis played a crucial role in the absorption process. Additionally, endocytosis of IN-LIP-CS/PA was mediated through clathrin, lipid raft, caveolin, and macropinocytosis. Furthermore, the endoplasmic reticulum and Golgi apparatus were mainly involved in the intracellular transport of IN-LIP-CS/PA. The combination of MCT1-mediated endocytosis and the intracellular transport pathways may help IN-LIP-CS/PA avoid lysosomal degradation, thereby improving the intracellular transport efficiency of insulin. In vivo studies demonstrated that IN-LIP-CS/PA achieved a significantly better hypoglycemic effect. These findings suggested that the newly developed bilayer liposome delivery system holds promise as an effective platform for the oral delivery of insulin.