In a study published in Science Advances, a team led by Prof. LIANG Xingjie from the National Center for Nanoscience and Technology of the Chinese Academy of Sciences developed site-specific adaptive milk-derived nanovesicles (MiNVs) which survive the gastrointestinal environment, cross the intestinal epithelium, and release insulin specifically in the liver, enabling efficient oral insulin delivery.

Diabetes is a chronic metabolic disease. 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 it faces major challenges such as the harsh gastrointestinal environment, the low permeability of the intestinal epithelium, and hepatic clearance of foreign particles.

In this study, researchers developed MiNVs capable of binding natural immunoglobulin G (IgG) on their surface. This binding allowed 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 triggered the cleavage of 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 the 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 the Food and Drug Administration (FDA)-approved liposomal materials, MiNVs combine the advantages of biosafety, scalability, and cost-effectiveness.

This study highlights a promising strategy to mimic endogenous insulin secretion through oral delivery.