In recent years, significant focus has been placed on the negative impacts of nanoplastics on living organisms. However, nanoplastics at environmental concentrations may interact with drugs, leading to more severe side effects in organisms. This study used Caenorhabditis elegans (C. elegans) to investigate how environmental levels (μg/L) of polystyrene nanoparticles (PS-NPs) influence tamoxifen toxicity and its mechanisms. Combined exposure to tamoxifen and PS-NPs significantly impaired locomotion, pumping, brood size, growth, and induced oxidative stress in both parents and offspring compared to single exposures. DAF-2 mutations conferred resistance, while DAF-16 mutations increased susceptibility. The combined exposure promoted DAF-16::GFP nuclear translocation and decreased SOD-3::GFP and HSP-16.2::GFP fluorescence, indicating toxicity through the DAF-2/DAF-16 IIS pathway. Bacterial metabolism was also linked to the toxic effects, feeding C. elegans metabolically inactivated OP50 significantly reduced the toxicity associated with the combined exposure of PS-NPs and tamoxifen. Additionally, dietary N-acetyl-L-cysteine significantly improved resistance to combined PS-NP and tamoxifen exposure. In summary, this study highlights how long-term exposure to environmental nanoplastic levels can enhance drug side effects, providing new insights into nanoplastics' role in drug interactions.

Keywords: Caenorhabditis elegans; N‐acetylcysteine; insulin/IGF‐1; oxidative stress; polystyrene nanoparticles; tamoxifen.

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