Institute of Quantitative Biology, Department of Physics, Zhejiang University, Hangzhou 310027, China.
Nanoscale. 2019 Nov 28;11(46):22293-22304. doi: 10.1039/c9nr04358f.
Molybdenum disulfide (MoS2), a representative hexagonal transition metal dichalcogenide (TMD), has been extensively exploited in biomedical applications due to its unique physicochemical properties and biocompatibility. However, the lack of adequate data regarding how MoS2 activates immunological responses of macrophages remains a key concern for its risk assessment. Here, we employ a combined theoretical and experimental approach to investigate the interactions of MoS2 and PEGylated MoS2 (MoS2-PEG) with macrophages. We first perform molecular dynamics simulations to examine the atomic-detailed interactions of MoS2 and MoS2-PEG nanoflakes with a realistic model of the macrophage membrane. We show that a small MoS2 nanoflake (edge length of 2.86 nm) is capable of penetrating the macrophage membrane independent of its concentration. We also demonstrate that when initiated with a corner point-on configuration, the surface-bound PEG chains of MoS2-PEG hinder its membrane insertion process, leading to a prolonged passage through the membrane. Moreover, when placed in a face-on arrangement initially, the MoS2-PEG exhibits a lower binding free energy than pristine MoS2 after its adsorption on the membrane surface. The PEG chains can even insert and get buried in the outer leaflet of the membrane, providing additional contact for membrane adsorption. Our flow cytometric experiments then show that the responses of macrophages to either MoS2-PEG or MoS2 are significantly higher than that of the control (no nanomaterial stimulus), with MoS2-PEG eliciting stronger cytokine secretion than the pristine MoS2. The characteristics of slower/prolonged membrane penetration and stronger membrane adsorption of MoS2-PEG compared to pristine MoS2 explain why it triggers more sustained stimulation and higher cytokine secretion in macrophages as observed in our experiments. Our findings reveal the underlying molecular mechanism of how MoS2-PEG influences the immune responses and suggest its potential applications in nanomedicine involving immune stimulation.
二硫化钼（MoS2），一种代表性的六方过渡金属二硫属化物（TMD），由于其独特的物理化学性质和生物相容性，已在生物医学应用中得到广泛开发。然而，由于缺乏关于 MoS2 如何激活巨噬细胞免疫反应的充分数据，因此其风险评估仍然是一个关键问题。在这里，我们采用理论和实验相结合的方法来研究 MoS2 和聚乙二醇化 MoS2（MoS2-PEG）与巨噬细胞的相互作用。我们首先进行分子动力学模拟，以检查 MoS2 和 MoS2-PEG 纳米片与巨噬细胞膜的实际模型的原子细节相互作用。我们表明，一个小的 MoS2 纳米片（边长为 2.86nm）能够独立于其浓度穿透巨噬细胞膜。我们还表明，当以角点-on 构型起始时，MoS2-PEG 的表面结合的 PEG 链阻碍其膜插入过程，导致其在膜中穿过的时间延长。此外，当最初以面-on 排列放置时，MoS2-PEG 在吸附到膜表面后，其结合自由能低于原始 MoS2。PEG 链甚至可以插入并埋入膜的外叶，为膜吸附提供额外的接触。然后，我们的流式细胞术实验表明，巨噬细胞对 MoS2-PEG 或 MoS2 的反应明显高于对照（无纳米材料刺激），MoS2-PEG 引起的细胞因子分泌比原始 MoS2 更强。与原始 MoS2 相比，MoS2-PEG 具有较慢/延长的膜穿透和更强的膜吸附特性，这解释了为什么它在我们的实验中会在巨噬细胞中引发更持续的刺激和更高的细胞因子分泌。我们的研究结果揭示了 MoS2-PEG 如何影响免疫反应的潜在分子机制，并暗示了其在涉及免疫刺激的纳米医学中的潜在应用。
