This study explores the use of acoustic nanobubbles to enhance the precision and effectiveness of ultrasound neuromodulation in mice. By delivering PEGylated gas vesicles (PGVs) to specific brain regions, the researchers were able to locally activate neurons and evoke targeted behaviors. The PGVs, coated with poly(ethylene glycol) (PEG), improved water solubility and biocompatibility, allowing for stable delivery and prolonged retention in the brain. Ultrasound stimulation, combined with PGVs, activated mechanosensitive ion channels, leading to reversible calcium signaling and increased c-Fos expression in the targeted regions. This method successfully triggered limb movement and altered specific locomotor behaviors, such as rotation and freezing, by targeting the motor cortex and deep brain regions like the dorsal striatum. Additionally, PGVs-actuated ultrasound stimulation reduced depression-like behaviors in a mouse model by selectively activating serotonin neurons in the dorsal raphe nucleus (DRN). The biosafety assessment showed no significant cytotoxicity or systemic toxicity, indicating the potential for safe and effective neuromodulation without genetic modification. Overall, this study demonstrates a non-invasive, spatially targeted, and temporally precise method for neuromodulation using ultrasound and nanobubbles.This study explores the use of acoustic nanobubbles to enhance the precision and effectiveness of ultrasound neuromodulation in mice. By delivering PEGylated gas vesicles (PGVs) to specific brain regions, the researchers were able to locally activate neurons and evoke targeted behaviors. The PGVs, coated with poly(ethylene glycol) (PEG), improved water solubility and biocompatibility, allowing for stable delivery and prolonged retention in the brain. Ultrasound stimulation, combined with PGVs, activated mechanosensitive ion channels, leading to reversible calcium signaling and increased c-Fos expression in the targeted regions. This method successfully triggered limb movement and altered specific locomotor behaviors, such as rotation and freezing, by targeting the motor cortex and deep brain regions like the dorsal striatum. Additionally, PGVs-actuated ultrasound stimulation reduced depression-like behaviors in a mouse model by selectively activating serotonin neurons in the dorsal raphe nucleus (DRN). The biosafety assessment showed no significant cytotoxicity or systemic toxicity, indicating the potential for safe and effective neuromodulation without genetic modification. Overall, this study demonstrates a non-invasive, spatially targeted, and temporally precise method for neuromodulation using ultrasound and nanobubbles.