In a study published in Science Advances, a research team led by Prof. LIANG Xing-Jie from the National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences developed site-specific adaptive milk-derived nanovesicles (MiNVs) that enable efficient oral insulin delivery by surviving the gastrointestinal environment, crossing the intestinal epithelium, and releasing insulin specifically in the liver.
Diabetes is a chronic metabolic disease that currently affects more than 800 million adults worldwide. For patients with type 1 diabetes (T1D) or advanced type 2 diabetes, routine insulin injections remain the standard treatment. However, subcutaneous administration is invasive, reduces long-term compliance, and bypasses the liver's first-pass regulation, leading to side effects such as peripheral hyperinsulinemia.
Oral insulin delivery offers a patient-friendly approach compared with the conventional subcutaneous administration but the harsh gastrointestinal environment, the low permeability of the intestinal epithelium, and hepatic clearance of foreign particles remain key challenges in this area.
The researchers overcame these challenges by developing MiNVs capable of binding natural immunoglobulin G (IgG) on their surface. The capability to bind IgG allows the nanovesicles to exploit the neonatal Fc receptor (FcRn) pathway for transcytosis across intestinal epithelial cells while evading lysosomal degradation. Once transported into the liver, elevated biothiol levels trigger cleavage of the disulfide bonds, releasing insulin in a site-specific manner before premature clearance.
In streptozotocin-induced T1D animal models, MiNVs achieved an oral insulin bioavailability of 20.4% in rats, which was about 20 times higher than that of free insulin, and 13.3% in minipigs, demonstrating effective glycemic control during both short-term and long-term treatment. Importantly, no long-term toxicity was observed even after high-dose repeated administration.
The high performance of MiNVs is attributed to their dual adaptability: FcRn-mediated transepithelial transport and biothiol-responsive liver-specific insulin release. By integrating naturally derived exosomes with FDA-approved liposomal materials, MiNVs combine biosafety, scalability, and cost-effectiveness, making them highly translatable for clinical applications.
This study highlights a promising strategy to mimic endogenous insulin secretion through oral delivery. Moreover, the modular and site-specific adaptive nature of the MiNVs platform may extend its utility beyond insulin to the oral delivery of other therapeutic biomacromolecules like peptides, proteins, and nucleic acids.
Schematic Diagram: MiNVs designed for efficient oral insulin delivery (Image by XIA Bozhang et al)
Contact: LIANG Xing-Jie
National Center for Nanoscience and Technology (NCNST)
E-mail: liangxj@nanoctr.cn
