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. MoS2 nanosheets trigger lung inflammation that is fast recovered, although the products derived from their degradation remain in the alveolar macrophages and in the extracellular vesicles for up to 30 days. The in vivo biotransformation of MoS2 is caused by reactive oxygen species following three mechanisms: scrolling, etching, and oxidation, generating molybdate ions and oxide nanoparticles.