Abstract Nanomaterials emerged as boundless resource of innovation, but their shape and biopersistence related to respiratory toxicology raise longstanding concerns. The development of predictive safety tests for inhaled nanomaterials, however, is hampered by limited understanding of cell type-specific responses. To advance this knowledge, we used single-cell RNA-sequencing to longitudinally analyze cellular perturbations in mice, caused by three carbonaceous nanomaterials of different shape and toxicity upon pulmonary delivery. Focusing on nanomaterial-specific dynamics of lung inflammation, we found persistent depletion of alveolar macrophages by fiber-shaped nanotubes. While only little involvement was observed for alveolar macrophages during the initiation phase, they emerged, together with infiltrating monocyte-derived macrophages, as decisive factors in shifting inflammation towards resolution for spherical nanomaterials, or chronic inflammation for fibers. Fibroblasts, central for fibrosis, sensed macrophage and epithelial signals and emerged as orchestrators of nanomaterial-induced inflammation. Thus, the mode of actions identified in this study will significantly inspire the precision of future in vitro testing. Graphical abstract

Cell circuits underlying nanomaterial specific respiratory toxicology