Oxidative stress is a critical event in neuronal damage following seizures. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to be promising nanotherapeutic agents in neurological disorders. However, the mechanism underlying MSC-EVs therapeutic efficacy for oxidative stress-induced neuronal damage remains poorly understood. Methods: We investigated the antioxidant and restoration activities of MSC-EVs on hippocampal neurons in response to H₂O₂ stimulation in vitro and seizures in vivo. We also explored the potential underlying mechanism by injecting adeno-associated virus (AAV)-nuclear factor erythroid-derived 2, like 2 (Nrf2), a key antioxidant mediator, in animal models. Results: MSC-EVs were enriched in antioxidant miRNAs and exhibited remarkable antioxidant activity evident by increased ferric ion-reducing antioxidant ability, catalase, superoxide dismutase, and glutathione peroxidase activities and decreased reactive oxygen species (ROS) generation, DNA/lipid/protein oxidation, and stress-associated molecular patterns in cultured cells and mouse models. Notably, EV administration exerted restorative effects on the hippocampal neuronal structure and associated functional impairments, including dendritic spine alterations, electrophysiological disturbances, calcium transients, mitochondrial changes, and cognitive decline after oxidative stress in vitro or in vivo. Mechanistically, we found that the Nrf2 signaling pathway was involved in the restorative effect of EV therapy against oxidative neuronal damage, while AAV-Nrf2 injection attenuated the antioxidant activity of MSC-EVs on the seizure-induced hippocampal injury. Conclusions: We have shown that MSC-EVs facilitate the reconstruction of hippocampal neurons associated with the Nrf2 defense system in response to oxidative insults. Our study highlights the clinical value of EV-therapy in neurological disorders such as seizures.

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