Gallud Audrey, Delaval Mathilde, Kinaret Pia, Marwah Veer Singh, Fortino Vittorio, Ytterberg Jimmy, Zubarev Roman, Skoog Tiina, Kere Juha, Correia Manuel, Loeschner Katrin, Al-Ahmady Zahraa, Kostarelos Kostas, Ruiz Jaime, Astruc Didier, Monopoli Marco, Handy Richard, Moya Sergio, Savolainen Kai, Alenius Harri, Greco Dario, Fadeel Bengt
Institute of Environmental Medicine Karolinska Institutet Stockholm 171 77 Sweden.
Faculty of Medicine and Health Technology Tampere University Tampere 33720 Finland.
Adv Sci (Weinh). 2020 Oct 11;7(22):2002221. doi: 10.1002/advs.202002221. eCollection 2020 Nov.
Despite considerable efforts, the properties that drive the cytotoxicity of engineered nanomaterials (ENMs) remain poorly understood. Here, the authors inverstigate a panel of 31 ENMs with different core chemistries and a variety of surface modifications using conventional in vitro assays coupled with omics-based approaches. Cytotoxicity screening and multiplex-based cytokine profiling reveals a good concordance between primary human monocyte-derived macrophages and the human monocyte-like cell line THP-1. Proteomics analysis following a low-dose exposure of cells suggests a nonspecific stress response to ENMs, while microarray-based profiling reveals significant changes in gene expression as a function of both surface modification and core chemistry. Pathway analysis highlights that the ENMs with cationic surfaces that are shown to elicit cytotoxicity downregulated DNA replication and cell cycle responses, while inflammatory responses are upregulated. These findings are validated using cell-based assays. Notably, certain small, PEGylated ENMs are found to be noncytotoxic yet they induce transcriptional responses reminiscent of viruses. In sum, using a multiparametric approach, it is shown that surface chemistry is a key determinant of cellular responses to ENMs. The data also reveal that cytotoxicity, determined by conventional in vitro assays, does not necessarily correlate with transcriptional effects of ENMs.
尽管付出了巨大努力，但驱动工程纳米材料（ENM）细胞毒性的特性仍知之甚少。在此，作者使用传统体外试验结合基于组学的方法，研究了一组31种具有不同核心化学组成和多种表面修饰的ENM。细胞毒性筛选和基于多重分析的细胞因子谱分析显示，原代人单核细胞衍生的巨噬细胞与人类单核细胞样细胞系THP-1之间具有良好的一致性。低剂量细胞暴露后的蛋白质组学分析表明，细胞对ENM存在非特异性应激反应，而基于微阵列的分析揭示了基因表达随表面修饰和核心化学组成的变化而发生显著改变。通路分析突出显示，具有阳离子表面且表现出细胞毒性的ENM会下调DNA复制和细胞周期反应，同时上调炎症反应。这些发现通过基于细胞的试验得到了验证。值得注意的是，某些小的、聚乙二醇化的ENM被发现无细胞毒性，但它们会诱导类似于病毒的转录反应。总之，使用多参数方法表明，表面化学是细胞对ENM反应的关键决定因素。数据还显示，传统体外试验所确定的细胞毒性不一定与ENM的转录效应相关。
