On the effect of ligand shell heterogeneity on nanoparticle/protein binding thermodynamics.

Nonspecific protein adhesion to nanoparticle (NP) has been proven to have important implications in nanomedicine. However, there are only a few examples of careful studies relating protein binding thermodynamics to NP physicochemical features. In particular, a systematic investigation of how NP/protein binding parameters scale with size for sub-10 nm NPs and whether this scaling is affected by the surface feature of NPs remain unaddressed. Previously, we have developed an analytical ultracentrifugation (AUC) based method to determine NP/protein binding thermodynamic parameters that was shown to be particularly effective for sub-10 nm NPs. In this work, we exclusively utilize this method to investigate the binding parameters for a well-defined set of gold NPs with varying size and surface ligand ratios to the model protein human serum albumin. We find that gold NPs with a homogenous distribution of hydrophilic molecules in their ligand shell have a monotonic dependence of their binding constants and of the maximum number of bound proteins as a function of their surface area. On the other hand, a more complex relation is found for particles with patchy ligand shell. The findings of this research highlight the significance of surface morphology on the interplay between protein binding behavior and NP size.