Effect of ligand and shell densities on surface structure of core-shell nanoparticles self-assembled from function-spacer-lipid constructs

Biomolecular corona is the major obstacle in clinical translation of nanomedicines. To overcome this problem, comprehensive studies of the processes leading to the formation of a biomolecular corona are required. Since such dynamical studies require high spatial and temporal resolution, nanoparticles utilized in it should enable combined experimental and simulation studies. Interactions at nano-bio interface are defined by nanoparticle surface properties such as topography, charge and surface chemistry. Hence, as the preliminary step towards deep understanding of the processes of corona formation it is necessary to develop nanoparticles employing various biocompatible materials and characterize their surface properties. In this work, we applied molecular dynamics simulation to study surface structure of organic core-shell nanoparticles formed by self-assembly of synthetic molecules composed of DOPE lipid, carboxymethylglycine spacer and biotin. Lipid moieties form the hydrophobic core, spacer motifs serve as a hydrophilic shell and biotin residues function as targeting ligand. By mixing such function-spacer-lipid, spacer-lipid and lipid-only constructs at various molar ratios, densities of the ligand and spacer on nanoparticle surface were modified. For convenient analysis of the structure and dynamics of all regions of nanoparticles’ surface, we compiled topography maps based on atomic coordinates. It was shown that an increase in the density of the shell does not reduce exposure of the core, but increases shell average thickness. Biotin, due to its alkyl valeric acid chain and spacer flexibility, is localized primarily near the hydrophobic core and its partial presentation on the surface occurs only in nanoparticles with higher ligand densities. However, an increase in biotin density leads to its clustering. In turn, ligand clustering diminishes stealth properties of the shell and targeting efficiency. Based on nanoparticle surface structures we determined the optimal density of biotin. Experimental studies reported in the literature confirm these conclusions. We also suggest design tips to achieve preferred biotin presentation. Simulation results are consistent with the synchrotron SAXS profile. We believe that such studies will contribute to the better understanding of nano-bio interactions towards the rational design of efficient drug delivery systems.