Polystyrene nanoplastics exacerbate systemic lupus erythematosus via neutrophil extracellular traps (NETs) formation.

Nanoplastics (NPs) are ubiquitous environmental pollutants capable of penetrating biological barriers and disrupting immune homeostasis. However, their immunotoxic potential to trigger or exacerbate autoimmune diseases (AIDs), such as systemic lupus erythematosus (SLE), remains largely unexplored. Herein, using polystyrene NPs (PS-NPs) as a model, we systematically investigated their immunotoxicity and underlying mechanisms exacerbating SLE progression via neutrophil extracellular traps (NETs). Initiating with human data, we observed that SLE patients exhibited significantly decreased neutrophils and increased serum NETs, closely correlating with disease activity. In vitro toxicological assessments revealed that neutrophils rapidly internalized PS-NPs, triggering concentration- and time-dependent cell death specifically driven by NET formation. In vivo, using environmentally relevant, human-equivalent exposure doses, orally administered PS-NPs heavily accumulated in the liver and kidneys of lupus-prone mice. This exposure dose-dependently elevated systemic NET levels and profoundly aggravated SLE manifestations, including severe renal lesions, hepatosplenomegaly, and elevated autoantibodies levels. Furthermore, serum metabolomic profiling uncovered that PS-NPs amplified lipid and amino acid dysregulation, highlighting a metabolic dimension to NP-induced immunotoxicity. Crucially, pharmacological inhibition of this pathway using cyclophosphamide (CTX) or dihydroartemisinin (DHA) successfully mitigated the PS-NPs-exacerbated phenotypes, supporting the potential involvement of NETs in this environmental toxicity. Collectively, our findings identify environmental PS-NP exposure as a significant risk factor for AID exacerbation, providing critical mechanistic evidence to inform human health risk assessments for susceptible populations.