Neurotoxic Domino Effect: Dietary Silica Nanoparticles Spark Microglial Extracellular Traps and Neuronal Pyroptosis.

Silica nanoparticles (SiO-NPs) are increasingly detected in environmental and food systems, raising concerns about their potential health risks via dietary exposure. Neurotoxicity assessment of SiO-NPs is a critical aspect, yet the mechanisms underlying their neurotoxic effects remain poorly understood. This study examined depression-like behaviors in mice following 21-day oral administration of three distinct-sized SiO-NPs (1 μm, 300 nm, and 50 nm), with particular focus on microglia-neuron crosstalk. The results demonstrate that SiO-NPs disrupt blood-brain barrier integrity, induce microglial release of inflammatory extracellular traps (ETs) accompanied by neuronal pyroptosis, and ultimately cause depression-like behaviors in mice, with effects negatively correlating with particle size. Mechanistically, SiO-NPs uptake by microglia promoted ROS-driven M1/M2 polarization imbalance and ETs release, while neuronal pyroptosis was mediated via the ROS/NLRP3 axis. Coculture experiments confirmed that microglial ETs exacerbated neuronal pyroptosis, and neuronal pyroptosis induced M1 polarization of microglia and further ETs release, ultimately forming a domino effect of neuroinflammation. These findings clarify key mechanisms underlying SiO-NPs-induced neurotoxicity, providing critical insights for exposure risk assessment in food applications.