Controlling Macrophage Uptake of Gold Nanoparticles through the Design of an Effective Heterogeneous Coating.

Self-assembled monolayers (SAMs) on gold nanoparticles (AuNPs) enable the rational tailoring of their surface properties, a key feature with high relevance in biomedical applications. However, establishing direct links between the structure of SAMs at the molecular level and nanoparticle characteristics remains experimentally challenging, calling out for complementary computational techniques. Here, we integrate experimental techniques such as differential centrifugal sedimentation and electrophoretic light scattering with coarse-grained simulations to gain structural information for (mixed)-SAMs that present a varying degree of disorder at their hydrophilic, solvent-exposed interface. We propose a design strategy to control the disorder in the hydrophilic region of negatively charged SAMs that goes beyond the use of standard thiolated ethylene glycol oligomers. Our simulations show that the coating with the highest chain-length heterogeneity is characterized by superior hydration and a more diffuse electric double layer. These subtle differences, which become evident only by integrating experimental data with numerical predictions, have a large impact on the extent of nanoparticle internalization by macrophages. Through the elucidation of the structure-function relationship, this work provides a robust framework for the SAM composition optimization on nanoparticles.