Zinc Oxide Nanoparticle-Induced Neurotoxicity: Underlying Molecular Mechanisms and Future Perspectives

The expanding application of zinc oxide nanoparticles (ZnO NPs) in consumer products, medicine, and the food industry has raised significant concerns regarding their potential neurotoxicity. This review synthesizes current understanding of the pathways by which ZnO NPs gain access to the central nervous system (CNS), their resulting neurotoxic effects, and the underlying molecular mechanisms. These nanoparticles primarily breach the CNS via translocation across the blood–brain barrier, axonal transport along sensory nerves, and disruption of the microbiota–gut–brain axis. Upon entry, ZnO NPs induce behavioral deficits, including impaired learning, memory, and motor function, alongside pathological brain damage. The neurotoxicity is driven by a multi-faceted mechanism involving mitochondrial dysfunction, oxidative stress, energy depletion, and neuroinflammation, often triggered by the release of Zn2+ ions. Furthermore, ZnO NPs can activate diverse cell death pathways, including apoptosis, ferroptosis, and pyroptosis. Critically, their neurotoxic potential is intrinsically linked to their physicochemical properties, such as size and shape. Emerging evidence also suggests that ZnO NP exposure may promote the aggregation of pathological proteins like Tau, thereby potentially increasing the risk for neurodegenerative diseases. Finally, we discuss potential mitigation strategies, such as surface modification and intervention with natural compounds. This review underscores the need for a refined risk assessment of ZnO NPs to ensure their safe deployment.