Molecular dynamics simulations of oleuropein diffusion in chitosan‐based nanoparticles

BACKGROUND: This study explores the diffusion mechanisms of oleuropein (OLE), a promising polyphenolic compound, within chitosan-based nanoparticles using molecular dynamics simulations. Chitosan nanoparticles serve as drug delivery carriers, leveraging biocompatibility and tunable release properties influenced by environmental factors such as pH. Focusing on two systems – acidic and neutral – we analyzed the initial stages of OLE release, assessing interactions between OLE, chitosan, water molecules, and acetate ions. RESULTS: Simulations revealed that acidic nanoparticles, with protonated amino groups, exhibited enhanced electrostatic interactions and hydration, favoring an initial swelling that acts as the primary driver for eventual OLE diffusion. In contrast, neutral nanoparticles demonstrated weaker hydration and slower OLE release. Specifically, the diffusion coefficients for OLE in the acidic bulk was found to be approximately 26 × 10−7 cm2 s−1, significantly higher than in the neutral bulk (13.6 × 10−7 cm2 s−1). Conversely, in the neutral system, a ‘polymer wrapping’ effect hinders diffusion. CONCLUSION: These findings highlight that, in acidic media, matrix expansion takes precedence over molecular diffusion as the primary driver for release. This mechanistic insight suggests that modulating the initial protonation state is a key strategy for optimizing chitosan nanocarriers and controlling burst release profiles. © 2026 The Author(s). Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).