Enhanced Epithelial Cell Uptake of Glycol Chitosan‐Coated PLGA Nanoparticles for Oral Drug Delivery

It is reported that poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NPs) coated with chitosan and its derivatives, such as glycol chitosan (GC), can enhance the targeted uptake of PLGA NPs by intestinal epithelial cells. However, the optimal amount of GC for coating and the specific mechanisms by which it facilitates PLGA endocytosis remain unclear. In this study, PLGA‐NPs are prepared using either single‐ or double‐emulsion methods and coated with varying amounts of GC. The results confirmed that GC‐coated PLGA NPs are internalized via both clathrin‐mediated and caveolae‐mediated endocytosis, whereas uncoated NPs relied on only clathrin‐mediated endocytosis in Caco‐2 and HT‐29 cells. The optimized GC‐coated PLGA‐NPs formulation is further modified by layering alginate to enhance the oral delivery of insulin. In subsequent in vivo studies, the GC and alginate‐coated PLGA NPs demonstrated stability and prolonged efficacy, achieving approximately a 50% reduction in blood glucose levels at 6 h post‐administration in streptozotocin‐induced diabetic mice. These findings provide compelling evidence of the optimal coating amount and molecular mechanisms for GC in the PLGA oral platform, underscoring the feasibility and commercial potential of oral delivery platform based on the optimized GC‐ and alginate‐coated PLGA NPs.