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Abstract：
As a representative two-dimensional (2D) nanomaterial, graphene oxide (GO) has shown high potential in many applications due to its large surface area, high flexibility, and excellent dispersibility in aqueous solutions. These properties make GO an ideal candidate for bio-imaging, drug delivery, and cancer therapy. When delivered to the body, GO has been shown to accumulate in the liver, the primary accumulation site of systemic delivery or secondary spread from other uptake sites, and induce liver toxicity. However, the contribution of the GO physicochemical properties and individual liver cell types to this toxicity is unclear due to property variations and diverse cell types in the liver. Herein, we compare the effects of GOs with small (GO-S) and large (GO-L) lateral sizes in three major cell types in liver, Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatocytes. While GOs induced cytotoxicity in KCs, they induced significantly less toxicity in LSECs and hepatocytes. For KCs, we found that GOs were phagocytosed that triggered NADPH oxidase mediated plasma membrane lipid peroxidation, which leads to PLC activation, calcium flux, mitochondrial ROS generation, and NLRP3 inflammasome activation. The subsequent caspase-1 activation induced IL-1β production and GSDMD-mediated pyroptosis. These effects were lateral size-dependent with GO-L showing stronger effects than GO-S. Amongst the liver cell types, decreased cell association and the absence of lipid peroxidation resulted in low cytotoxicity in LSECs and hepatocytes. Using additional GO samples with different lateral sizes, surface functionalities, or thickness, we further confirmed the differential cytotoxic effects in liver cells and the major role of GO lateral size in KUP5 pyroptosis by correlation studies. These findings delineated the GO effects on cellular uptake and cell death pathways in liver cells, and provide valuable information to further evaluate GO effects on the liver for biomedical applications.
摘要：
作为具有代表性的二维纳米材料,氧化石墨烯（GO）由于其表面积大，在许多应用中显示出很高的潜力，高灵活性,在水溶液中具有优异的分散性。这些特性使GO成为生物成像的理想候选者，药物输送,和癌症治疗。当被送到身体时，GO已经显示在肝脏中积累，全身输送的主要积累部位或其他吸收部位的次要传播，并诱导肝脏毒性。然而,由于肝脏的性质变化和不同的细胞类型，GO的理化性质和单个肝细胞类型对这种毒性的贡献尚不清楚。在这里，我们比较了小（GO-S）和大（GO-L）横向大小在肝脏三种主要细胞类型的效果，库普弗细胞(KCs)，肝窦内皮细胞（LSEC），和肝细胞。虽然GO在KCs中诱导细胞毒性，它们在LSECs和肝细胞中诱导的毒性显著降低。对于KC，我们发现GO被吞噬，触发了NADPH氧化酶介导的质膜脂质过氧化，这导致PLC激活，钙通量，线粒体ROS产生，和NLRP3炎性体激活。随后的胱天蛋白酶-1激活诱导IL-1β产生和GSDMD介导的焦亡。这些效应是横向尺寸依赖性的，GO-L显示出比GO-S更强的效应。在肝细胞类型中，细胞结合减少和不存在脂质过氧化导致LSECs和肝细胞的低细胞毒性。使用具有不同横向尺寸的附加GO样品，表面功能，或厚度，我们通过相关研究进一步证实了肝细胞中的不同细胞毒性作用以及GO侧向大小在KUP5焦亡中的主要作用。这些发现描绘了GO对肝细胞中细胞摄取和细胞死亡途径的影响，并提供有价值的信息，以进一步评估GO对肝脏的影响，用于生物医学应用。
