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

Abstract

With the rapid development of carbon-based two-dimensional 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.

Cytocompatibility of Ti3C2Tx MXene with Red Blood Cells and Human Umbilical Vein Endothelial Cells and the Underlying Mechanisms

“…Although the surface of GO also contains C–O–C, −OH, −COOH, and CO groups, a large area of unoxidized regions (sp 2 domain) remains as illustrated by the characterizations using ultra-high-resolution transmission electron microscopy in several previous literature studies. − Specifically, Gómez-Navarro et al reported that the unoxidized regions of GO can reach ∼60%. Therefore, the strong direct vdW attractions coordinated with hydrophobic interactions between those unoxidized regions with the lipid hydrophobic tails can still destroy the cell membrane. , In addition, the keen-edged corners of GO nanosheets should also facilitate their cell membrane damage effects, promoting hemolytic activity (Figure S4). The important role of these sharp corner sites in assisting GO nanosheets to penetrate cell membranes had been thoroughly illustrated previously by combining multiscale modeling and imaging experiments …”

“…Therefore, the strong direct vdW attractions coordinated with hydrophobic interactions between those unoxidized regions with the lipid hydrophobic tails can still destroy the cell membrane. 69 , 76 In addition, the keen-edged corners of GO nanosheets should also facilitate their cell membrane damage effects, promoting hemolytic activity ( Figure S4 ). The important role of these sharp corner sites in assisting GO nanosheets to penetrate cell membranes had been thoroughly illustrated previously by combining multiscale modeling and imaging experiments.…”

Converting Nanotoxicity Data to Information Using Artificial Intelligence and Simulation

“…MD simulations revealed that the endocytosis of graphene occurred via flat vesiculation and graphene self-rotation (Figure F) . Graphene suspended outside the cell membrane can destructively extract numerous lipids from the membrane and induce lipid depletion, membrane damage, and finally cytotoxicity (Figure G). − These distinctive pathways of graphene interactions with cell membrane suggest that the NM–cell membrane interactions are strongly dependent on the NM’s physicochemical properties and the microenvironment, as will be discussed in the following section.…”