It is now well known that the interaction between nanoparticulate systems and biological fluids leads to deposition of various proteins onto the surface of the nanoparticles (NPs), hence, formation of a protein “corona”. Arrangement of the associated proteins on the surface of NPs defines the in vivo response of material to the surrounding biologic environment. In order to predict the intercellular fate of NPs, therefore, it is essential to have an in-depth insight into the factors influencing the protein corona composition. While remarkable progress has been made in elucidating the factors that affect hard corona composition, the actual intercellular pathways that particles undertake in vivo and their dependence on the corona composition have not been investigated. In this study, we demonstrated that variation in plasma concentration can significantly change the biological fate of NPs, through alteration in the composition of the protein shell. For this purpose, sulfonated polystyrene and silica NPs were interacted with human plasma and fetal bovine serum in gradient concentrations. In contrast to the hard coronas formed under conventional static plasma conditions, large differences were observed in the amounts and affinities of proteins when particles were maintained under the plasma gradient conditions. This finding can help scientists to have a better understanding of the nanoparticle–cell interactions in vivo and elucidate the safety considerations for biomedical applications, resulting in nano-biomaterials that are “safe by design”.
