Deep Brain Stimulation by Blood–Brain-Barrier-Crossing Piezoelectric Nanoparticles Generating Current and Nitric Oxide under Focused Ultrasound

Neurodegenerative diseases entail the gradual breakdown of the central nervous system, leading to involuntary movements, cognitive decline, and memory issues. Deep brain stimulation (DBS), a successful treatment, uses implanted electrodes to modify neural signals and neurotransmitter release, though invasive electrode insertion poses side effects. Therefore, a wireless, non-invasive approach is essential. Piezoelectric materials generate electrical output when mechanically stimulated. Combining these materials with focused ultrasound might non-invasively stimulate localized neurons. However, the blood-brain barrier (BBB), a critical CNS barrier, limits nanoparticle delivery to the brain. A strategy to modulate BBB is crucial for effective treatment. Nitric oxide (NO), a vital gas molecule, shows potential in disrupting BBB, but the mechanism remains unclear. A NO release in response to specific stimuli could temporarily open BBB, facilitating nanoparticle accumulation in target areas. This study introduces a multifunctional system, combining ultrasound-responsive NO donors with piezoelectric nanoparticles for non-invasive neural stimulation. These nanoparticles release NO and direct current only under ultrasound, temporarily disrupting BBB for nanoparticle accumulation. The piezoelectric nanoparticles stimulate dopaminergic neurons. In an animal model, systemically administered nanoparticles under high-intensity focused ultrasound alleviated Parkinson’s disease symptoms without toxicity. In conclusion, this innovative approach offers promise for non-invasive, wireless neural stimulation.