Protein-nanostructure interactions in drug delivery systems: insights from molecular dynamics simulations

Protein-based therapeutics have become an important part of modern medicine, offering highly specific and effective treatments for a wide range of diseases and improving patients' quality of life compared with many conventional small-molecule drugs. Owing to their macromolecular nature, the successful administration of these agents has consistently faced significant challenges. The rapid advancement of nanotechnology in recent decades has encouraged the development of innovative and cost-effective nanostructured systems designed to improve protein stability, protection, and targeted delivery. Direct observation of underlying phenomena at the subatomic scale between nanostructures and proteins is usually not feasible in experimental setups; in this context, molecular modeling techniques such as molecular dynamics (MD) have paved the way for revealing the molecular mechanisms governing protein-nanostructure interactions and stability. In this review, we summarize recent computational studies on protein-nanostructure interactions with different classes of nanomaterials, including biocompatible polymers (chitosan, PLGA), inorganic nanoparticles (AuNPs, ZnONPs), and carbon-based materials (SWCNTs, C60). These investigations demonstrate that MD simulations can explain mechanisms of adsorption, encapsulation, conformational stability, structural change, and protein corona formation, thus supporting the rational design of improved nanocarriers. Despite the growing interest in nanomedicine, MD investigations of lipid-based nanostructures remain relatively limited, even though these systems are widely used in pharmaceutical formulations. We further discuss the important factors affecting the accuracy and predictive capability of MD simulations, including force field selection, system representation, simulation timescale, and molecular resolution. Future progress needs transferable parameters, improved pH-dependent modeling, and the integration of multiscale simulation methods to capture complex phenomena like protein corona formation.