The molecular mechanism of robust macrophage immune responses induced by PEGylated molybdenum disulfide

Abstract

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.