New Evidence for the Mechanisms of Nanoplastics Amplifying Cadmium Cytotoxicity: Trojan Horse Effect, Inflammatory Response, and Calcium Imbalance

Nanoplastics (NPs) are emerging pollutants worldwide. Particularly worrisome is that although studies have reported that NPs can amplify the biotoxicity of environmental pollutants, the specific mechanism remains unclear. Here, we found that NPs, even without significant toxicity (cell survival: 99.11%), amplified the hepatocyte toxicity of Cd²⁺. Mechanistically, higher Cd²⁺ uptake (Δ = 23.80%) combined with crucial intracellular desorption behavior of Cd²⁺ loaded in NPs (desorption rate: 82.70%) were identified as prerequisites for NPs amplifying Cd²⁺ cytotoxicity. As for toxigenic pathways, the inflammatory response and calcium (Ca) signaling pathway were identified as the primary molecular events leading to the amplification of Cd²⁺ cytotoxicity. Further phenotypic monitoring revealed that NPs synergized with Cd²⁺ to induce more severe pyroptosis and apoptosis by activating the inflammatory caspase-1-dependent and Ca²⁺-mitochondrial-caspase-3 pathways to a greater extent, respectively. This study reveals and proves for the first time the "Trojan horse" effects of NPs, thus elucidating the actual mechanisms by which NPs act as toxicity amplifiers of pollutants, providing significant insights into accurate risk assessment of NPs in composite pollution.