Iron Oxide Nanoparticle Coatings Dictate Cell Outcomes Despite the Influence of Protein Coronas

A critical issue in nanomedicine is to understand the complex dynamics that dictate the interactions of nanoparticles (NPs) with their biological milieu. The most exposed part of a nanoparticle is its surface coating, which comes into contact with the biological medium and adsorbs proteins, forming what is known as a protein corona (PC). It is assumed that this PC mainly dictates the nanoparticle-cell interactions. As such, we set out to analyze how different coatings on iron oxide nanoparticles (MNPs) affect the composition of the PC that forms on top of them, and how these newly formed coronas influence the uptake of MNPs by macrophages and tumor cells, their subcellular location upon internalization, and their intracellular degradation. We found that different superficial charges of the coatings did not affect the PC composition, with an enrichment in proteins with affinity for divalent ions regardless of the type of coating. The iron oxide core of the MNP might become exposed to the biological medium, influencing the proteins that constitute the PCs. The presence of enzymes with hydrolase activity in the PC could explain the degradation of the coatings when they come into contact with the biological media. In terms of MNP internalization by cells, coatings mainly determine the endocytic pathways used, especially in terms of receptor-mediated endocytosis. However, the increase in hydrodynamic size provoked by the formation of the associated corona drives uptake mechanisms like macropinocytosis. Once inside the cells, the PC protected the NPs in their intracellular transit to lysosomes, where they were fully degraded. This understanding of how coatings and PCs influence different cellular processes will help design improved NPs for biomedical applications, taking into account the influence of the coating and corona on the biology of the NPs.