Copper-based nanoparticles-associated neurotoxicity: ions or particles?

The widespread use of engineered nanomaterials raises concerns regarding their potential toxicity to human health and the environment. Among metal oxide nanoparticles, copper-based nanoparticles (Cu-based NPs) are extensively produced and utilized due to their unique physicochemical properties. The dissolution of NPs leads to the release of ionic species, and still, there is no clear consensus on whether metal-based NPs' toxicity arises primarily from the nanoparticles themselves or from the ionic species generated through metal ion dissolution. This study systematically evaluated the cellular uptake and toxicological profiles of various Cu-based NPs (Cu, CuO, Cu₂O, and CuFe₂O₄) in comparison to ionic copper (CuCl₂) using the PC12 neuronal model. ICP-MS analysis demonstrated that cellular uptake was both dose- and particle-dependent; notably, CuO NPs yielded the highest intracellular copper accumulation. Cytotoxicity assays (MTT and NRU) revealed that all Cu-based NPs showed significantly higher toxicity than CuCl₂. Furthermore, Cu-based NP exposure, particularly with Cu₂O, triggered a robust oxidative stress response characterized by significant alterations in GSH, CAT, and MDA levels. This oxidative imbalance was closely associated with a marked increase in apoptosis and necrosis and substantial DNA damage. Our findings elucidate that the oxidation state and chemical formulation of copper nanoparticles significantly dictate their neurotoxic potential, with Cu₂O NPs exhibiting the most pronounced geno- and cytotoxicity. These results highlight the necessity of considering nanoparticle-specific effects beyond simple ion dissolution in the safety assessment of engineered nanomaterials.