SiO2 nanoparticles disrupt neurodevelopmental processes in human midbrain organoids in a redox-suppressed, non-cytotoxic manner.

Silicon dioxide nanoparticles (SiO₂-NPs) are widely used in food, cosmetics, and biomedical products and cross the placental barrier, raising concerns about their potential developmental toxicity. Although previous studies have documented cytotoxic and oxidative effects of SiO₂-NPs in adult tissues, their influence on early human neurodevelopment remains poorly understood. Here, we employed human midbrain organoids (mBOs) derived from pluripotent stem cells to investigate SiO₂-NP-induced neurodevelopmental alterations during dopaminergic lineage formation. Exposure during this critical window reduced organoid growth, suppressed neural progenitor proliferation, and downregulated dopaminergic markers, while overall neuronal populations were preserved. Remarkably, these changes occurred without apoptosis but were accompanied by diminished intracellular ROS, impaired calcium signaling, and activation of astrocytic and inflammatory pathways. Phospho-kinase profiling and RNA sequencing further revealed suppression of calcium- and redox-dependent signaling networks alongside metabolic and inflammatory reprogramming. Collectively, these findings identify a non-cytotoxic, redox-suppressed mechanism by which SiO₂-NPs perturb neuronal maturation and connectivity, highlighting the developmental vulnerability of the human midbrain to nanoparticle exposure.