Sono-mechanical nanostructures-enabled sustained precise ultrasound brain stimulation

Ultrasound can enable deep brain neuromodulation with high spatiotemporal resolution, comparable to well-known modalities like TMS, tDCS, and tACS. However, conventional transcranial ultrasound still lacks the precision needed to modulate a small set of neurons. Here, we introduce hollow silica nanostructures (HSN) that localize and amplify ultrasonic effects for long-term neuromodulation in male mice brains (>9 weeks) by activating mechanosensitive ion channels. By controlling the HSN amount and delivery site, ultrasound can selectively activate targeted brain regions, including M1, striatum, VTA, and STN, at time points ranging from days to weeks, and relieve PD motor symptoms in mice models, without evident toxicity. Overall, our stimulation approach offers a safe, minimally-invasive strategy for effective chronic neuromodulation without genetic modification, with notable therapeutic applications. Conventional transcranial ultrasound often lacks the precision needed to modulate a small set of neurons. Here, the authors demonstrate that hollow silica nanostructures can locally amplify ultrasound, and enable sustained and precise stimulation of deep brain circuits in mice, offering a minimally invasive, nongenetic platform for targeted neuromodulation.