Exploration of a dual-mimetic mucus inert nanocomplex for enhanced oral insulin delivery

The development of oral insulin delivery systems has advanced significantly, with polyelectrolyte nanocomplexes (PEC) showing promise due to their solvent-free synthesis. However, their efficacy is limited by poor mucus penetration and intestinal absorption. Inspired by the nature of mucin, chitosan (CS) modified with proline, threonine and serine to mimic the mucin's PTS sequence were synthesized to enhance mucus permeability of the PEC. To further improve the mucus permeability and the trans-epithelial transport of the PEC, muco-penetrating nanocomplexes were fabricated by utilizing hyaluronic acid (HA), thus forming a surface with high-density positive and negative charges to mimic the surface charge properties of viruses. The nanocomplexes were self-assembled using modified CS and insulin, followed by HA coating. It was demonstrated that the nanocomplexes exhibited good physical stability, enhanced protection against enzymatic degradation, and increased penetration efficiency across the mucus layer and small intestine compared to unmodified counterparts. Furthermore, the in vivo hypoglycemic study further revealed a 2.16-fold increase in relative pharmacological availability for the nanocomplexes over the CS/Ins PEC Collectively, these findings reveal the potential of (PTS-CS/Ins)/HA, a dual-mimicking muco-penetrating nanocomplex based on the nature of mucin and virus, as a promising platform for oral insulin delivery.