Abstract: nanoplastics (NPs) have emerged as ubiquitous environmental contaminants, yet their long-term immunological consequences in vertebrates remain mechanistically uncharacterized. Using adult zebrafish exposed to environmentally relevant and high concentrations of polystyrene NPs (PS-NPs), we used single-cell RNA sequencing, flow cytometry, and functional immune assays to comprehensively dissect NP-induced immune dysregulation. Single-cell transcriptomic analysis revealed that while overall kidney immune cell frequencies remained stable, chronic NP exposure profoundly reprogrammed hematopoietic stem and progenitor cell differentiation trajectories toward myeloid-biased differentiation, indicating impaired lymphoid regeneration capacity. Concurrently, NPs induced global activation of infection-associated and programmed cell death pathways across immune populations despite the absence of microbial challenge, establishing a state of sterile inflammation in which NP particles function as danger-associated molecular patterns. At the cellular level, NP exposure selectively depleted regulatory T cells while expanding NK cell populations, coupled with marked suppression of pro-inflammatory cytokines and Treg-associated immunoregulatory genes, creating a dysbalanced inflammatory state. Mechanistically, antigen-presenting cells (APCs) from NP-exposed fish indicated severely impaired antigen uptake and suppressed co-stimulatory molecule expression. Consequently, T cells exhibited transcriptional exhaustion characterized by baseline downregulation of effector cytokines and complete ablation of antigen-responsive gene upregulation, resulting in severely diminished T cell proliferation following antigen stimulation in a dose-dependent manner. These multi-scale mechanistic findings establish that chronic NP exposure causes an organized immune dysfunction distinct from cytotoxic immune depletion. This study provides single-cell resolution evidence of NP-induced immunotoxicity and highlights the urgent need for environmental and health risk assessments of chronic NP contamination.

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