Intranasal Zinc Oxide Nanoparticles Induce Neuronal PANoptosis via Microglial Pathway

Abstract Recent data have revealed an increased risk of respiratory exposure during the manufacturing process and application of nanomaterials, resulting in an increased incidence of neurodegenerative diseases in the general population. Zinc oxide nanoparticles (ZNPs) are among the most used nanomaterials in biomedical and manufactured consumer products. In this study, neurological dysfunction after intranasal administration of ZNPs is observed, in which the ZNPs enter the brain via the nose‐to‐brain pathway and accumulate in microglia but not in astrocytes or neurons. By using a coculture system of microglia and neurons, the ZNPs are found that induce microglia‐derived oxidative stress injury and lead to neuronal cell PANoptosis. In this context, ZNPs induced the generation of reactive oxygen species (ROS) originating from microglial NADPH oxidase 2 (NOX2), which further induced neuronal membrane lipid peroxidation and increased Ca 2+ influx and mitochondrial DNA release. The leaked mitochondrial DNA subsequently initiates PANoptosis of neurons. Importantly, inhibition of microglial NOX2 activation can significantly alleviate brain oxidative injury and rescue neuronal PANoptosis. This study can advance the understanding of the mode of neuronal cell death while underscoring the importance of the interconnections among glial cells and neurons, which is beneficial for informing effective interventions for respiratory exposure to nanoparticles.