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.