Sulfidation Affects Macrophage Uptake of Metal-Based Nanomaterials by Dictating Protein Corona Compositions and Aggregation States Collectively

Metal-based nanomaterials are one of the most widely used classes of nanomaterials. Understanding their human exposure is critical for the risk management of these nanomaterials. Once released into the environment, metal nanomaterials are prone to undergo sulfidation. This process significantly alters the physicochemical properties of the nanomaterials and subsequently, dictates the extents and pathways of exposure. Here, we show that sulfidation of nanosized Ag, ZnO, CuO, and Cu₂O affects their macrophage uptake to varied degrees, by differentially regulating protein corona compositions and aggregation states of the nanomaterials. Sulfidation-induced changes in hydrodynamic diameters determine whether macrophage uptake occurs through endocytosis or phagocytosis. For a given uptake pathway, the extents of uptake depend on macrophage recognition of protein corona, the compositions of which are largely influenced by sulfidation. Specifically, increased abundance of transferrin and low-density apolipoprotein C2 in the corona as affected by sulfidation promotes clathrin-mediated endocytosis, while the enrichment of complement factor H facilitates uptake by complement receptor-mediated phagocytosis. The findings advance our understanding on the nanospecific mechanisms governing environmental behaviors and implications of nanomaterials, and further underline the importance of taking into account the aging processes in the risk management of these materials.