Oral liver-targeted delivery systems for anti-hyperglycemic therapy: From passive to active targeting strategies

Diabetes is a highly prevalent chronic disease worldwide. Traditional insulin injection is inconvenient, driving oral insulin as a promising research area. However, oral insulin delivery encounters multiple physiological barriers in the gastrointestinal tract. As an indispensable organ for glucose metabolism, the liver serves as one of the key targets for insulin to exert its hypoglycemic effects. Thus, the development of liver-targeted delivery systems provides a novel strategy for improving insulin efficacy and reducing side effects. This technology is expected to promote the preferential utilization of insulin in the liver by mimicking physiological insulin secretion patterns, thereby effectively enhancing hypoglycemic effects while lowering the risk of hypoglycemia. This article reviewed the research progress in oral liver-targeted insulin delivery and its application in the treatment of diabetes and related complications, highlighting active and passive liver-targeting strategies. Passive liver targeting mainly relies on the synergy between the physicochemical properties of nanocarriers and the unique anatomical characteristics of the liver, achieving non-specific accumulation of insulin in hepatocytes. In contrast, active liver targeting is accomplished by modifying specific ligands on the carrier surface, which mediate receptor-mediated endocytosis via specific recognition and binding between ligands and receptors on the hepatocyte surface, thereby enabling precise enrichment of insulin in targeted hepatocytes. The advantages and application prospects of these two targeting strategies were analyzed to provide a theoretical basis for the research and development of oral insulin formulations, facilitate their clinical translation, and offer more effective and convenient therapies for diabetic patients.