Ultrasound-driven piezoelectric nanomaterial platform enables wireless neuromodulation for Parkinson’s disease

Parkinson's disease (PD) is characterized by progressive dysfunction of the basal ganglia circuitry, leading to both motor and cognitive impairments. Current neuromodulation strategies for deep brain targets remain highly invasive and lack precise spatiotemporal controllability. For example, traditional deep brain stimulation offers substantial relief from PD's movement-related symptoms by surgically placing electrodes in the subthalamic nucleus (STN), but this procedure carries substantial risks including intracranial hemorrhage and infection. Herein, we report an ultrasound-driven piezoelectric neuromodulation platform for minimally invasive regulation of STN-associated circuitry in PD. Barium titanate piezoelectric nanoparticles (BTNPs) with a typical non-centrosymmetric tetragonal phase were fabricated and stereotactically delivered into the STN. Upon ultrasound stimulation, BTNPs generated localized microelectric signals through piezoelectric conversion for wireless modulation of neuronal activity. Ultrasound-activated BTNPs modulated neuronal activity within the STN-associated basal ganglia circuitry and increased movement-evoked dopamine release in the striatum, suggesting improved nigrostriatal dopaminergic function. These effects were accompanied by increased tyrosine hydroxylase expression and reduced dopaminergic neuronal loss in the substantia nigra. Following a one-week treatment with targeted STN neuromodulation, PD mice showed significant enhancements in both motor and cognitive abilities. Collectively, this work establishes a controllable and minimally invasive piezoelectric strategy for deep-brain neuromodulation and provides mechanistic insight into STN-associated circuit regulation in PD. STATEMENT OF SIGNIFICANCE: Deep brain stimulation is effective for Parkinson's disease (PD) but requires surgically implanted electrodes and battery-powered pulse generators. Here, we present an ultrasound-driven piezoelectric nanomaterial platform that enables wireless neuromodulation of deep brain regions. Barium titanate piezoelectric nanoparticles were stereotactically delivered into the subthalamic nucleus, where ultrasound stimulation triggered localized electromechanical transduction, enabling neuronal modulation without implanted electrodes. In an MPTP-induced PD mouse model, this approach alleviated motor and cognitive deficits, restored pathological neural activity, and enhanced movement-evoked dopamine release. Furthermore, chemogenetic manipulation confirmed that subthalamic nucleus activity mediates these therapeutic effects. This study establishes a biomaterial-enabled strategy for wireless deep brain neuromodulation and advances non-electrode-based neuromodulation for PD.