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

Abstract

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.

Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective

“…Ball milling of bulk MoS 2 in the presence of bile salts was associated with the ultrasonication-assisted exfoliation in water at 0 °C. 56 This avoids the use of toxic chemicals and solvents. Alternatively, electrochemical methods are commonly combined with ultrasonication-assisted exfoliation.…”

“…The production of 2H-MoS 2 nanosheets was performed using less conventional approaches such as microwave irradiation. , Exfoliation of TMDs can be also achieved by combining more than one approach. Ball milling of bulk MoS 2 in the presence of bile salts was associated with the ultrasonication-assisted exfoliation in water at 0 °C . This avoids the use of toxic chemicals and solvents.…”

“…In line with these results, aggregated MoS 2 induced neutrophil recruitment via secretion of CXC chemokine, IL-6, and MCP-1 at 40 h. At 21-day post exposure, there was evidence of inflammation resolution for the aggregated MoS 2 group, and none of the tested materials induced fibrosis despite the higher TGF-β content in bronchoalveolar lavage (BAL) fluids for both MoS 2 . In another study, mice were intratracheally exposed to MoS 2 nanosheets (with lateral sizes in the range 50–150 nm) and sacrificed at 0.5–28 days after exposure to a bolus dose of 50 μg . BAL fluids showed increased levels of macrophages and neutrophils at 12 h, which reduced after 1 day.…”

“…(c) STEM sequence from in situ liquid etching of MoS 2 sheets in DPBS-H 2 O 2 solution. (d) Sequence from in situ liquid STEM displaying internal etching from edge defects of a single MoS 2 sheet . Reproduced with permission from Ortiz Pena, N.; Cherukula, K.; Even, B.; Ji, D. K.; Razafindrakoto, S.; Peng, S.; Silva, A. K. A.; Menard-Moyon, C.; Hillaireau, H.; Bianco, A.; Fattal, E.; Alloyeau, D.; Gazeau, F., Resolution of MoS 2 Nanosheets-Induced Pulmonary Inflammation Driven by Nanoscale Intracellular Transformation and Extracellular-Vesicle Shuttles.…”

“…In contrast with WS 2 and TiS 2 , MoS 2 showed biodegradation in the liver and almost complete excretion after one month through urine and feces possibly due to the oxidation of MoS 2 into water-soluble molybdate species like MoO 4 . This is in agreement with the aforementioned mouse study in which in vivo degradation of MoS 2 in the lungs was shown with partial excretion of nanoparticles by way of extracellular vesicles . With the aim of developing a drug delivery system, the distribution of MoS 2 and PEG-MoS 2 showed predominant accumulation of both nanomaterials in RES with a long retention time of more than 30 days for MoS 2 .…”