Scheme 1.

Illustration of epileptogenesis, LTG-loaded micelle formation and regulation of pathological microenvironment in epileptic foci. The gradual transformation from a formerly healthy brain into one suffering from autonomous seizures, named epileptogenesis, can be divided into three phases: (A) First, a serious insult, for example, stroke or head trauma, initiates molecular and cellular changes in the affected brain regions. (B) Second, within those foci, glial cells are pathologically activated (i.e., gliosis) to establish inflammatory microenvironment and release cytokines, chemokines, growth factors and other molecules to reduce or repair brain damages. However, unrestrained reactive gliosis may cause excessive inflammation, neuronal death and tissue damage and last until acute, unprovoked seizures occur. (C) Third, after continuous inflammation and recurring seizures, molecular and cellular changes can hardly be reversed and give rise to neural death. Our nano-medicine will (1) penetrate the BBB with the help of GLUT1-targeting ligand DHAA and then (2) release lamotrigine under the stimulation from high concentration of ROS in epileptic lesions. (3) Lamotrigine is delivered to prevent aberrant firing while ROS-scavenger phenylboronic ester can reduce oxidative stress to alleviate chronic inflammation. (4) Finally, epileptogenesis will hopefully be terminated due to our nano-medicine's protection to neurons and stabilizing effect on glia.