ACS APPL MATER INTER

Upon contact with biological fluids like serum, a proteincorona(PC) complex forms on iron oxide nanoparticles (IONPs) in physiologicalenvironments and the proteins it contains influence how IONPs actin biological systems. Although the biological identity of PC-IONPcomplexes has often been studied in vitro and in vivo, there have been inconsistent results due to thedifferences in the animal of origin, the type of biological fluid,and the physicochemical properties of the IONPs. Here, we identifieddifferences in the PC composition when it was derived from the seraof three species (bovine, murine, or human) and deposited on IONPswith similar core diameters but with different coatings [dimercaptosuccinicacid (DMSA), dextran (DEX), or 3-aminopropyl triethoxysilane (APS)],and we assessed how these differences influenced their effects onmacrophages. We performed a comparative proteomic analysis to identifycommon proteins from the three sera that adsorb to each IONP coatingand the 10 most strongly represented proteins in PCs. We demonstratedthat the PC composition is dependent on the origin of the serum ratherthan the nature of the coating. The PC composition critically affectsthe interaction of IONPs with macrophages in self- or non-self identitymodels, influencing the activation and polarization of macrophages.However, such effects were more consistent for DMSA-IONPs. As such,a self biological identity of IONPs promotes the activation and M2polarization of murine macrophages, while a non-self biological identityfavors M1 polarization, producing larger quantities of ROS. In a humancontext, we observed the opposite effect, whereby a self biologicalidentity of DMSA-IONPs promotes a mixed M1/M2 polarization with anincrease in ROS production. Conversely, a non-self biological identityof IONPs provides nanoparticles with a stealthy character as no cleareffects on human macrophages were evident. Thus, the biological identityof IONPs profoundly affects their interaction with macrophages, ultimatelydefining their biological impact on the immune system.