A Neuronal Signal Sorting and Amplifying Nanosensor for EEG‐Concordant Imaging‐Guided Precision Epilepsy Ablation

Abstract Surgery remains an essential treatment for managing drug‐resistant focal epilepsy, but its accessibility and efficacy are limited in patients without distinct structural abnormalities on magnetic resonance imaging (MRI). Potassium ion (K + ), a critical marker for seizure‐associated neuronal signaling, shows significant promise for designing sensors targeting hidden epileptic foci. However, existing sensors cannot cross the blood‐brain barrier and lack the ability to specifically enrich and amplify K + signals in the brain with high temporal and spatial resolution. Here, an intravenously administered neuronal signal sorting and amplifying nanosensor (NSAN) is reported that combines real‐time dynamic reversible K + fluorescence imaging with high‐resolution structural MRI, enabling electroencephalogram‐concordant imaging of MRI‐negative epileptic foci. Guided by NSANs, minimally invasive surgery is successfully performed in both intrahippocampal kainic acid (KA) epilepsy model with foci confined to the ipsilateral hippocampus, and intraperitoneal KA model where foci are randomly distributed, resulting in sustained seizure control and cognitive improvement. These findings highlight the NSAN as a transformative tool for visualizing hidden epileptic foci, thereby broadening eligibility for minimally invasive and precision surgical intervention.