Macrophage membrane‒biomimetic nanoparticles target inflammatory microenvironment for epilepsy treatment.

The clinical treatment of epilepsy is faced with challenges. On the one hand, the effectiveness of existing antiepileptic drugs (AEDs) is limited by the blood‒brain barrier (BBB); on the other hand, changes in the inflammatory microenvironment during epileptogenesis are often neglected. The death-associated protein kinase 1 inhibitor TC-DAPK6 and the fluorescent probe rhodamine B were encapsulated in hollow mesoporous silica nanocarriers (HMSNs), which were then coated with a macrophage membrane to prepare macrophage membrane-biomimetic nanoparticles, namely, MA@RT-HMSNs. biotoxicity, cellular uptake, BBB permeability and inflammatory targeting ability were evaluated in cells. The effects of MA@RT-HMSN treatment were explored by immunohistochemistry, TUNEL assay, Western blot analysis, quantitative real-time polymerase chain reaction, electroencephalogram recording and behavioural tests in kainic acid-induced acute and chronic epilepsy model mice. MA@RT-HMSNs showed excellent biocompatibility both and . MA@RT-HMSNs successfully crossed the BBB and exhibited increased efficacy in targeted delivery of TC-DAPK6 to inflammatory lesions in epileptic foci. Macrophage membrane coating conferred MA@RT-HMSNs with higher stability, greater cellular uptake, and enhanced TC-DAPK6 bioavailability. Furthermore, MA@RT-HMSNs exerted beneficial therapeutic effects on acute and chronic epilepsy models by alleviating microenvironment inflammation, preventing neuronal death, and inhibiting neuronal excitability and gliosis. MA@RT-HMSNs target inflammatory foci to inhibit death-related protein kinase 1 and exert antiepileptic effects. This study provides a promising biomimetic nanodelivery system for targeted epilepsy therapy.