Oral Insulin Enhanced by Dual-Ligand-Modified Nanoparticles via Trans-Golgi Network-Mediated Transport.

Oral insulin delivery is challenged by a cascade of gastrointestinal barriers, including mucus entrapment, poor apical endocytosis, extensive lysosomal degradation, and insufficient basolateral exocytosis. To overcome these obstacles in a coordinated fashion, we engineered a dual-ligand PLGA nanoparticle (PLGA-Tf/BAC-NPs) decorated with transferrin (Tf) and the sorting peptide BAC (ADDIDLLK). Tf facilitates efficient apical endocytosis via transferrin receptor (TfR) recognition, whereas BAC not only participates in AP-2-mediated internalization but, more critically, reroutes intracellular trafficking to evade lysosomal destruction. Mechanistically, BAC sequentially recognizes GGA-1 and AP-1, directing nanoparticles from endosomes to the trans-Golgi network (TGN) and subsequently to the basolateral membrane. This synergistic ligand pairing also endows the nanoparticles with rapid mucus-penetrating capability, as corroborated by nanoparticle tracking and mucin interaction assays. In a type 1 diabetic rat model, PLGA-Tf/BAC-NPs yielded a relative oral bioavailability of 16.62% and a pharmacological bioavailability of 7.58%, sustaining euglycemia for approximately 6 h. Collectively, our findings establish a clinically relevant PLGA-based platform that integrates a "mucus penetration-cellular uptake-intracellular trafficking" strategy, substantially advancing oral insulin delivery efficacy.