Ultrasound Active Piezoelectric Nanostimulators for Long‐Acting Wireless Deep Brain Electric Stimulation to Inhibit Epileptic Seizures

Electrical deep brain stimulation is effective for epilepsy suppression, but will lead to neural tissue damage and inflammation due to implantation of electrodes and a pulse generator. Transcranial magnetic and transcranial ultrasound stimulation cannot directly generate effective electrical signals in deep brain regions. Here, the use of piezoelectric nanoparticles is proposed as wireless nanostimulators for deep brain electrical stimulation and minimally invasive suppression of epilepsy. Polydopamine-coated barium titanate piezoelectric nanostimulators can adhere to neuronal membrane and generate pulsed electrical signals under ultrasound irradiation, effectively activating neurons through modulating voltage-gated calcium channels on the membrane. These nanostimulators can be minimal-invasively implanted into target deep brain regions, such as the hippocampal CA1, through stereotactic microinjection and remain stable for at least 14 weeks with negligible inflammatory reactions. These implanted nanostimulators precisely and effectively activate surrounding neurons and associated neural circuits in vivo under a portable low-intensity ultrasound transducer. This piezoelectric nanostimulator-based wireless deep brain electrical stimulation effectively suppresses epileptic seizures in both optogenetic and pilocarpine-induced epilepsy rat models. By combining the deep penetration of ultrasound with the efficacy of piezoelectric stimulation, this minimally invasive method holds great promise for effective suppression of epileptic seizures and management of other neural disorders.