Facet-dependent effect of engineered nanoceria on dopaminergic neurotoxicity and motor deficits involving glutathione depletion

Cerium dioxide (CeO 2 ) nanoparticles (NPs), bearing the switchable Ce 3+ /Ce 4+ redox pair, are attractive for applications in green energy and other fields. However, their potential toxicity, especially to the nervous system, remains poorly understood. The exposed facets and their surface chemistry, modulated by NPs morphology, play critical roles in their biological effects. In this study, the neurotoxic effects of CeO 2 NPs bearing different morphologies and surface chemistry (e.g., Ce 3+ /Ce 4+ ratio) were evaluated. Compared with the rod-shaped CeO 2 NPs (CeO 2 -Rod) and cube-shaped CeO 2 NPs (CeO 2 -Cube), the octahedron-shaped CeO 2 NPs (CeO 2 -Octa) exhibited the strongest pro-oxidant activity, associated with the lowest Ce 3+ /Ce 4+ ratio and inhibitory effect on glutathione (GSH) replenishment. 8-weeks oral exposure to CeO 2 NPs, especially the CeO 2 -Octa, induced significant motor dysfunction in mice. The underlying mechanism may involve CeO 2 -Octa-mediated deficient supply of GSH, which elevated the cellular reactive oxygen species (ROS) levels and led to dopaminergic neuron loss in the substantia nigra (SN). Transcriptomic analysis of the SN revealed alterations in oxidative stress, dopaminergic neurons, and mitochondrial function, and suppression of the PI3K/AKT pathway after CeO 2 -Octa exposure. Experiments with MN9D cell, a dopaminergic neuronal cell line, further confirmed that CeO 2 -Octa exhibited the most pronounced cytotoxicity and ROS overproduction. These findings underscore the facet-dependent neurotoxicity of CeO 2 NPs associated with disruption of the oxidative homeostasis, and identify surface chemistry as a critical parameter for predicting and mitigating nanomaterial safety.