Resolution of MoS₂ Nanosheets-Induced Pulmonary Inflammation Driven by Nanoscale Intracellular Transformation and Extracellular-Vesicle Shuttles

Pulmonary exposure to some engineered nanomaterials can cause chronic lesions as a result of unresolved inflammation. Among 2D nanomaterials and graphene, MoS₂ has received tremendous attention in optoelectronics and nanomedicine. Here an integrated approach is proposed to follow up the transformation of MoS₂ nanosheets at the nanoscale and assesss their impact on lung inflammation status over 1 month after a single inhalation in mice. Analysis of immune cells, alveolar macrophages, extracellular vesicles, and cytokine profiling in bronchoalveolar lavage fluid (BALF) shows that MoS₂ nanosheets induced initiation of lung inflammation. However, the inflammation is rapidly resolved despite the persistence of various biotransformed molybdenum-based nanostructures in the alveolar macrophages and the extracellular vesicles for up to 1 month. Using in situ liquid phase transmission electron microscopy experiments, the dynamics of MoS₂ nanosheets transformation triggered by reactive oxygen species could be evidenced. Three main transformation mechanisms are observed directly at the nanoscale level: 1) scrolling of the dispersed sheets leading to the formation of nanoscrolls and folded patches, 2) etching releasing soluble MoO₄ ^- , and 3) oxidation generating oxidized sheet fragments. Extracellular vesicles released in BALF are also identified as a potential shuttle of MoS₂ nanostructures and their degradation products and more importantly as mediators of inflammation resolution.