Insulin‐Loaded Muco‐Inert Nanoparticles Based on L ‐valine‐modified Chitosan and Fucoidan for Enhanced Oral Delivery

Oral delivery of insulin faces significant challenges due to various barriers present in the gastrointestinal tract, leading to minimal therapeutic outcomes. To overcome these obstacles, chitosan-based nanoparticles modified by L-valine were designed and subsequently coated with fucoidan (FU) to improve the permeation efficiency through the mucus layer and intestinal epithelium. The insulin-loaded nanoparticles were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), encapsulation efficiency (EE), and loading capacity (LC). The prepared nanoparticles VCS-INS-FU NPs, formed by L-valine-grafted chitosan (VCS) and fucoidan, can effectively resist the degradation of insulin by digestive enzymes and exhibit a sustained release profile of encapsulated insulin. Mucoadhesion tests revealed that the nanoparticles VCS-INS-FU NPs (INS/FU 1: 2) had significant mucus permeability. Furthermore, VCS-INS-FU NPs exhibited an enhanced capability for cellular internalization by cellular uptake studies using confocal laser scanning microscopy (CLSM). In vivo studies demonstrated that the oral insulin delivery system produced a pronounced and long-lasting hypoglycemia effect in diabetic mice. In conclusion, the muco-inert nanocomplex based on L-valine-modified chitosan and fucoidan presents a promising platform for effective oral insulin delivery.