▎ 摘　　要

Engineered nanomaterials (such as graphene oxide, GO) have shown great potential in biomedical applications as therapeutic and imaging agents. However, little is known about their potential transformations in biological settings, which may alter their physicochemical properties and consequently hinder their biomedical applications. Here, we show that GO undergoes a significant physicochemical transformation in two simulated human lung fluids-Gamble's solution and artificial lysosomal fluid (ALF), as the organic acids (e.g., citrate and acetate) in the lung fluids cause the reduction of GO, which is mainly due to the conversion of epoxy and carbonyl groups to phenolic groups. This biotransformation markedly inhibits the endocytosis of GO by scavenging macrophages. Notably, the alterations that occur in Gamble's solution enhance the layer-by-layer aggregation of GO, resulting in the precipitation of GO and a reduction in its interaction with cells, whereas the changes that occur in ALF lead to edge-to-edge aggregation of GO, thereby enhancing the adhesion of large sheet-like GO aggregates on the plasma membrane without cellular uptake. The varied interaction mechanisms with macrophages eventually induce different proinflammatory reactions. Experiments conducted in mice corroborated the morphological alterations of GO in a realistic lung microenvironment. Overall, the findings suggest that the biotransformation of nanomaterials may significantly alter their inherent properties and therefore affect their biosafety, such as the clearance of "worn-out" nanomaterials by immune cells, giving rise to potentially long-term side effects at the accumulation sites.