Deep brain stimulation by blood–brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound

Deep brain stimulation via implanted electrodes can alleviate neuronal disorders. However, its applicability is constrained by side effects resulting from the insertion of electrodes into the brain. Here, we show that systemically administered piezoelectric nanoparticles producing nitric oxide and generating direct current under high-intensity focused ultrasound can be used to stimulate deep tissue in the brain. The release of nitric oxide temporarily disrupted tight junctions in the blood–brain barrier, allowing for the accumulation of the nanoparticles into brain parenchyma, and the piezoelectrically induced output current stimulated the release of dopamine by dopaminergic neuron-like cells. In a mouse model of Parkinson’s disease, the ultrasound-responsive nanoparticles alleviated the symptoms of the disease without causing overt toxicity. The strategy may inspire the development of other minimally invasive therapies for neurodegenerative diseases.