Glycosylated nanoparticles for oral insulin delivery via glucose transporter to improve intestinal absorption

Oral administration offers significant advantages for insulin delivery, including improved patient compliance and convenience compared to injectable formulations. However, the therapeutic potential of oral insulin delivery is nevertheless constrained by multiple physiological barriers including gastrointestinal enzymatic degradation, mucus layer entrapment, and limited epithelial permeability. To protect against gastrointestinal degradation and promote penetration across the intestinal barrier, we developed glucose-modified PLGA-lipid hybrid nanoparticles through a sequential fabrication process involving insulin encapsulation in PLGA cores via W1/O/W2 double emulsion followed by surface functionalization with glycosylated lipids using film hydration-ultrasonication. The resulting core-shell nanoparticles combined protective and absorptive functions by maintaining insulin stability under gastric conditions while enabling pH-responsive intestinal release, with surface glucose moieties facilitating enhanced cellular uptake through glucose transporter-mediated pathways. In a type 1 diabetes mouse model this nanoparticle system demonstrated superior therapeutic outcomes, supporting its potential as an effective oral insulin delivery platform.