ROS-responsive glucosylated nanodisc prodrug for efficient targeted epilepsy therapy

Epilepsy, a global therapeutic challenge, is often drug-resistant due to poor blood–brain barrier (BBB) permeability of conventional antiepileptics, which also suffer from non-specific release and long-term safety issues. Here, a glucose-functionalized, reactive oxygen species (ROS)-responsive nanodisc system (GLND-TP) is presented, designed to overcome these via enhanced BBB traversal and epilepsy-specific drug release. It integrates GLUT1-targeting ligand (DSPE-PEG 2000 -Glucose) and glycaemic control (fasting-induced hypoglycemia plus glucose replenishment) to enhance GLUT1 expression/recycling. Incorporating ROS-cleavable phenytoin (PHT) prodrug (DSPE-PEG 2000 -TK-PHT), the 10–20 nm GLND-TP enables prolonged circulation, efficient BBB penetration, and ROS-triggered PHT release with ROS scavenging, alleviating oxidative stress and gliosis. In vivo, GLND-TP (0.1 mg/kg) achieves superior seizure suppression and reduced neural damage vs free PHT (10 mg/kg), with a 100-fold increase in potency. Mechanistically, it boosts local PHT bioavailability to inhibit pathological hyperexcitability and remodels epileptic microenvironment via ROS clearance. By bridging physiological targeting and pathological modulation, GLND-TP pioneers precision nanotherapy for neurological disorders, offering a translatable epilepsy-targeted strategy.