Impact of surface functionalization on the drug delivery performance of cellulose nanofibers and β-cyclodextrins: an in-silico study

In this study, an in-silico approach was employed, for the first time, to systematically evaluate modified linear and cyclic oligosaccharides as potential drug delivery systems for compounds with challenging pharmacokinetic profiles. Native β-cyclodextrin (β-CD) and a cellulose-based heptasaccharide, serving as cyclic and linear controls, respectively, were chemically modified with hydroxypropyl, hydroxyethyl, methyl, and acetyl groups. All nanocarriers were docked with curcumin, quercetin, resveratrol, and acyclovir. Subsequently, unloaded nanocarriers, drug–nanocarrier complexes, and free drugs were docked onto healthy, lung cancer, and inflamed membrane models to evaluate membrane binding. Drug docking onto nanocarrier revealed that carrier topology (linear or cyclic) was the primary determinant of binding affinity, followed by modification type. The acetylated β-CD formed the most favorable drug complex, likely due to the combined effects of preserved cavity geometry, enhanced hydrophobicity, favorable host–guest complementarity, van der Waals interactions, and distinct electrostatic environment within the cavity. During docking with membrane models, loaded and unloaded nanocarriers exhibited comparable binding energies, while methylation was generally unfavorable for drug loading and membrane interaction in linear and cyclic nanocarriers, respectively. Therefore, the curcumin–acetylated β-CD complex was further examined using a single 100-ns molecular dynamics trajectory, which showed structural stability of the drug and nanocarrier, persistent membrane adsorption, localized bilayer adaptation and preserved fluidity. MM/GBSA calculations indicated that membrane binding was favorable and predominantly van der Waals–driven, suggesting that acetylated β-CD may hold promise for drug loading and delivery. This approach supports the rational design and preliminary screening of nanocarrier-based drug delivery systems.