Nanomedicine for epilepsy: Expanding beyond conventional drug targets.

Abstract

Epilepsy remains a major neurological disorder characterized by unpredictable seizures and cumulative comorbidities that even endure with standard pharmacotherapy. Conventional antiepileptic drugs (AEDs) are constrained by two interrelated barriers: limited brain penetration due to the blood-brain barrier (BBB), which necessitates high systemic dosing and peripheral toxicity, and a narrow mechanistic focus on neuronal ion channels and synaptic receptors. This neuron-centric view overlooks non-neuronal drivers, such as neuroinflammation and BBB dysfunction, that sustain epileptogenesis and contribute to drug resistance in roughly one-third of patients. Nanomedicine addresses these limitations through a fundamentally different approach. Leveraging the unique advantages of nanocarriers, including facile synthesis, surface modification, and receptor-mediated BBB transcytosis, nanoparticles have evolved from passive delivery vehicles into intelligent, multifunctional therapeutic platforms that actively engage with disease biology. In this Perspective, we first delineate the inherent limitations of conventional AEDs in target selection. We then highlight how emerging nanomedicines are expanding the therapeutic target repertoire to include key non-neuronal nodes, with a focus on neuroinflammation and BBB repair. Finally, we offer a forward-looking perspective on two emerging frontiers: modulation of metabolic dysregulation and the microbiota-gut-brain axis, as well as the development of theranostic nanoplatforms that integrate real-time seizure monitoring with closed-loop intervention. Through this discussion, we aim to inspire a reorientation of nanomedicine strategies toward precision therapy for epilepsy.