Vascular bifurcation influences the protein corona composition on nanoparticles and impacts their cellular uptake

The protein corona (PC) that forms on nanoparticles (NPs) after in vivo injection influences their biodistribution, pharmacokinetics, and cell interaction. Although injected NPs traverse vascular networks, the impact of vascular features on the protein corona composition is mainly unexplored. Using an in vitro flow model that introduces bifurcations, a common feature of blood vessels, we show that vessels are not passive bystanders in the formation of the PC but that their features play active roles in defining the PC on NPs. The addition of bifurcation significantly increased the amount of proteins associated with NP. The bifurcation's introduction also changed the PC's composition on the NPs and affected the NP interactions with cells. Correlation analysis and modeling showed that these changes in the PC are mediated by both the branching and diameter reduction associated with vessel bifurcation and the resulting change in flow rate. The results indicate that blood vessel structures play an active part in the information of the PC, and their role should be studied critically for a better understanding of the PC and its biological implications.