Diving on the Surface of a Functional Metal Oxide through a Multiscale Exploration of Drug–Nanocrystal Interactions

While recent advances in nanotechnology offer significant possibilities for improving the development of targeted drug delivery systems (DDSs), the design of efficient nanocarriers remains challenging due to the complex interactions among nanoparticles, their surfaces, and therapeutic agents in biological environments. To shed light on such difficulties and provide an instrumental tool for the refinement of DDSs, this study presents a comprehensive computational and experimental approach for the development of zinc oxide nanocrystals (ZnO NCs), exploited as carriers for a hydrophobic drug used in the treatment of multiple myeloma (MM), namely, carfilzomib (CFZ). Oleic acid was adopted here as a stabilizing agent during the synthesis of iron-doped ZnO NCs, while aminopropyl groups were used as functionalizing moieties to improve drug adsorption. Advanced characterization techniques were employed to investigate the nanostructure and drug-loading properties. Furthermore, molecular modeling was exploited for elucidating the adsorption mechanism and the thermodynamics of the interactions between the drug and the NCs, offering a detailed understanding at the molecular level. These simulations provided predictive insights into possible molecular inactivation mechanisms and strategies to optimize the nanocarrier design, thus enabling tailored adjustments throughout the development process. While biological tests showed that CFZ-loaded ZnO NCs preserved the drug mechanism of action in MM cell lines, the interconnection between simulations and experiments played a central role in predicting and optimizing NCs–drug interactions. This approach demonstrates the potential of computational simulations in minimizing trial-and-error in the nanoconstruct development process, ultimately streamlining the creation and validation of more effective nanoparticle-based drug delivery systems.