Piezoelectric neuromodulation of the subthalamic nucleus ameliorates motor and nonmotor symptoms of Parkinson's disease.

Traditional deep-brain stimulation via implanted electrodes can effectively treat neurological disorders, but surgical injury limits its clinical application. Here, we developed ultrasound-responsive piezoelectric nanoparticles for minimal-invasive and wireless neuromodulation. In the 6-OHDA-induced Parkinson's disease (PD) mouse model, these nanoparticles are injected into the subthalamic nucleus (STN) of the mouse brain. After ultrasound stimulation for several days, the motor behavior, particularly gait abnormalities and nonmotor symptoms such as pain and anxiety, in PD mice is alleviated without detectable toxicity. The piezoelectric nanoparticles can activate the STN area of the mouse after ultrasound stimulation. Our results demonstrate that piezoelectric-mediated neuromodulation of the STN reverses motor deficits in PD by modulating neural signals, thereby protecting dopaminergic neurons and enhancing levels of the neurotransmitter dopamine. This process can rescue and mitigate mitochondrial dysfunction and neuroinflammation in the nigrostriatal pathway. Our approach enables STN neuronal activation with minimal invasiveness, offering a promising strategy for treating neurodegenerative diseases.