Exploring the stability and binding interactions of insulin in chitosan/alginate nanohydrogels

Abstract

Oral administration of insulin presents a desirable alternative to subcutaneous injection; however, achieving effective carrier-mediated protection of the peptide remains a significant challenge. In this study, we employed molecular dynamics (MD) simulations to investigate the encapsulation of insulin within three oral delivery systems at neutral pH: chitosan/alginate (CHI/ALG), deoxycholic acid-modified chitosan/alginate (CDA/ALG), and O-carboxymethyl chitosan/alginate (CMC/ALG). Building on previous experimental data, this work aimed to elucidate the atomic-level mechanisms governing insulin encapsulation. Previous MD studies have primarily focused on analyzing chitosan derivatives or isolated polysaccharides for insulin encapsulation; however, no prior research has directly compared multiple chitosan variants within a unified chitosan/alginate nanohydrogel system. Our results demonstrated that both CDA/ALG and CHI/ALG successfully encapsulated insulin, enhancing its structural stability. In contrast, the CMC/ALG system exhibited poor encapsulation performance, with insulin showing significantly less contact with the carrier and increased exposure to the surrounding environment, ultimately reducing its stability. In the effective systems, CDA and CHI formed stable nanoparticles around insulin, driven primarily by electrostatic, hydrophobic, and CH-π interactions. CDA, in particular, indicated greater residue-specific energy contributions, attributed to the self-assembly properties imparted by deoxycholic acid. Overall, CDA/ALG and CHI/ALG emerged as more promising candidates for oral insulin delivery. These findings provide valuable insights for the rational design of an environmentally friendly oral nanocarrier, with the potential to enhance insulin stability and bioavailability in the gastrointestinal tract.