Nanoplastics target lung monocytes, disrupting immune dynamics

Systemic exposure to microplastics and nanoplastics raises concerns about their biodistribution and impact on human health. Using whole-animal fluorescence imaging, flow cytometry, and single-cell RNA sequencing of nanoplastic-partitioned cells, we investigated the biodistribution and direct cellular responses to nanoplastics in female mice following systemic exposure. Unlike microplastics and iron nanoparticles, nanoplastics predominantly localized to the lung. In the lung, nonclassical monocytes and a distinct subpopulation of CD206^- interstitial macrophages selectively sequestered nanoplastics, whereas in the blood, sequestration was restricted exclusively to nonclassical monocytes. Notably, sequestering macrophages exhibited a delayed transition from nonclassical monocytes, as evidenced by the persistent expression of Plac8, Treml4, and Ace, which are key genes in the monocyte-to-interstitial macrophage transition. Depletion of monocytes triggered compensatory expansion of lung classical monocytes, which subsequently engaged in nanoplastic uptake. These findings reveal that nanoplastics perturb monocyte-to-macrophage differentiation and reprogram immune dynamics in the lung, implicating immune dysregulation as a potential long-term consequence of environmental nanoplastic exposure.