Curcumin - Gold Nanocomposites for Enhanced Doxorubicin Delivery: Molecular Mechanisms of Loading and Membrane Interactions

Abstract

Curcumin-functionalized gold nanoclusters are promising platforms for catalysis and drug delivery, however, the molecular determinants governing their stability, morphology, and solvent response remain poorly understood. Here, microsecond all-atom molecular dynamics simulations were employed to investigate a 2 nm gold nanoparticle noncovalently coated with different curcumin forms, including the neutral enol and trans-keto tautomers, the deprotonated enolate, and their mixtures in water-ethanol and water-methanol solvents. Region-resolved analyses of the radius of gyration, density profiles, and surface coverage reveal that neutral enol and trans forms generate compact assemblies with near-complete surface coverage, whereas enolate-rich systems adopt more expanded conformations with greater solvent exposure. Mixed systems preserve these intrinsic packing characteristics while improving overall surface coverage. Solvent substitution from ethanol to methanol reduces {pi}-{pi} stacking, strengthens Au-curcumin interactions, and increases surface coverage, yielding more compact nanostructures. Free energy and potential of mean force calculations further indicate that deprotonated curcumin most effectively screens Au-Au interactions and promotes nanoparticle dispersion, whereas the neutral tautomers provide moderate stabilization. Curcumin functionalization also enhances the loading of the anticancer drugs doxorubicin (DOX) and niraparib (NIR) onto Au nanoparticles. Membrane interaction with AuDOX/NIR-Curcumin simulations show that Enolate(An)-containing systems form more extended structures and interact more weakly with both negatively charged and neutral DMPC membranes. In contrast, neutral curcumin complexes form compact, positively charged assemblies with stronger interactions with the negatively charged model membrane. Furthermore, these interactions are predominantly driven by electrostatic attraction and are substantially weaker with the neutral DMPC membrane. Overall, these findings demonstrate how curcumin tautomeric state and solvent environment cooperatively govern interfacial organization and colloidal stability, drug-loading, and membrane interactions. This provides molecular-level design principles for curcumin-based gold nanocarriers for catalysis, sensing, and drug delivery applications.