Mimicking the transit of nanoparticles through the body: when the path determines properties at the destination

To test if the transit of a nanoparticle across different organs in the body affects its properties at the final destination, we devised an in vitro system that mimics the passage of nanoparticles from the blood to the lung to the brain and, occasionally, back to the blood. Each of the three media provided a unique corona to the nanoparticles, comprising mainly secreted, blood-specific proteins in the plasma and membrane proteins in the lung and the brain. The hard corona changed during the transit of the nanoparticle between different organs. Cellular uptake, antibacterial activity, and drug release kinetics were analyzed to assess the difference in the biological response to nanoparticles depending on the transit route. Drug release assays most consistently demonstrated the effects of the history of the nanoparticle passage across different media on its present properties. Both the uptake analysis and antibacterial assays showed that the key proteins for these two processes in the brain replace their analogues from the lung, but are ineffective in replacing the blood plasma content from the nanoparticle surface. Notwithstanding that some routes can erase the history of the passage of the nanoparticle across different organs, the route traversed by it mostly affects the properties it displays at the destination. A nanoparticle sent to a circular journey through an array of media can have different properties upon its return to the point of origin. History is an essential determinant of the properties of nanoparticles in biological milieus, the memory of which is inscribed in the nanoparticle corona.