Nonmonotonic Relationship between the Oxidation State of Graphene-Based Materials and Its Cell Membrane Damage Effects

With the rapid development of carbon-based twodimensional nanomaterials in biomedical applications, growing concern has emerged regarding their biocompatibility and especially their interactions with cell membranes. Our experimental studies found that the oxidation state, as one of the most important chemical parameters of graphene derivatives, regulates the hemolysis effect on human red blood cells in a nonmonotonic manner. Scanning electron microscopy and optical microscopy observations suggested that graphene oxides with medium oxygen content have the most serious destructive effects on the cell membranes. Molecular dynamics simulations and potential of mean force calculations revealed that, on the one hand, with the decrease in the surface oxygenated groups, more sp2 carbon area of graphene-based materials will be exposed, playing a facilitating role in the damage of cell membranes; on the other hand, fewer oxygenated groups also lead to the accumulation of graphene-based nanosheets in solutions. The formation of the multilayer structure of graphene-based nanosheets reduces the exposed sp2 carbon area, prevents the collective extraction of lipid molecules, and eventually results in a weakened extraction effect on cell membranes. Together, these factors generate a nonmonotonic relationship between the oxidation state of graphene oxides and their destructive effects on cell membranes.