Abstract

Epilepsy is one of the most common neurological disorders, with current antiepileptic drugs (AEDs) being ineffective in up to 30% of patients. Moreover, the therapeutic efficacy of existing AEDs is significantly limited by the blood–brain barrier (BBB). The neuropeptide Y2 receptor is a potential antiepileptic target, with NPY (3–36) acting as its selective agonist. GW2580, an inhibitor of the colony-stimulating factor 1 receptor, has neuroprotective potential. In this study, a novel nanocomposite, NPY@ZIF-RG, was synthesized by covalently conjugating NPY (3–36) onto the surface of GW2580-encapsulated nano-Zeolitic imidazolate framework-90 (ZIF-90) via a simple post-modification. The biosafety of NPY@ZIF-RG was evaluated in vitro and in vivo. The BBB permeability and its effects on neuroinflammation and neuronal excitability were assessed. The therapeutic efficacy of NPY@ZIF-RG was explored using immunohistochemistry, quantitative real-time polymerase chain reaction, and behavioral tests in a mouse model of kainic acid-induced acute epilepsy. The results indicated that NPY@ZIF-RG exhibited excellent biocompatibility and efficient BBB penetration. Furthermore, it exerted beneficial therapeutic effects by inhibiting microglia-mediated inflammation and reducing excitatory glutamate release. NPY@ZIF-RG alleviated hippocampal neuronal loss and cognitive dysfunction by co-delivering GW2580 and NPY (3–36), which exerted synergistic neuroprotective and anti-inflammatory effects. This study provides a promising nanocomposite drug-delivery system for the treatment of epilepsy.