Nanocage encapsulation improves antiepileptic efficiency of phenytoin

More than 30% of patients with epilepsy progress to drug-resistant epilepsy, leading to a significant increase in morbidity and mortality of epilepsy. The limitation of epileptic drug to reach the epileptogenic focus is the critical reason, and the blood-brain barrier (BBB) plays a crucial role. Here, we successfully constructed a hepatitis B core (HBc) protein nanocage (NC) with the insertion of brain target TGN peptide for facilitating epileptic drug phenytoin delivery to the brain. Our results demonstrated that this nanocage can specifically and efficiently target the brain tissue by 2.4 fold and increase the antiepileptic efficiency of phenytoin about 100 fold in pilocarpine induced models of epilepsy. Both in vivo mice and in vitro human neural three-dimensional cortical organoids demonstrated high penetration ability. These functions are achieved through the facilitation of brain target peptide TGN rather than disruption of brain blood barrier. In summary, we presented an efficient antiepileptic drug delivery nanocage for the treatment of refractory epilepsy. Moreover, this therapeutic modulation also provides promising strategy for other intractable neurological disease.