This study presents a novel method for non-invasive, targeted neuromodulation using nanobubble-actuated ultrasound in mice. The method utilizes optimized surface properties of PEGylated gas vesicles (PGVs) as ultrasonic actuators to achieve precise activation of specific brain regions. PGVs, when combined with ultrasound, enable localized activation of neurons through mechanosensitive ion channels, leading to reversible calcium signaling and increased c-Fos expression in targeted brain areas. This approach allows for the selective activation of motor cortex regions, evoking limb movements, and the activation of deep brain regions to elicit distinct behaviors such as rotation or freezing. The method also demonstrates therapeutic effects by selectively activating 5-HT neurons in the dorsal raphe nucleus (DRN), reducing depression-like behaviors in mice. PGVs are biocompatible, non-toxic, and do not interfere with normal brain function. The study shows that PGVs can enhance the spatial precision and temporal control of ultrasound neuromodulation, enabling targeted activation of deep brain circuits without genetic modification. The method is safe, with no observed cell damage or inflammation, and has potential applications in treating neurological disorders. The results indicate that PGVs-actuated ultrasound can precisely modulate specific neural circuits, induce distinct behaviors, and rescue neurological conditions. The study highlights the potential of nanobubble-mediated ultrasound as a promising, minimally-invasive approach for targeted neuromodulation.This study presents a novel method for non-invasive, targeted neuromodulation using nanobubble-actuated ultrasound in mice. The method utilizes optimized surface properties of PEGylated gas vesicles (PGVs) as ultrasonic actuators to achieve precise activation of specific brain regions. PGVs, when combined with ultrasound, enable localized activation of neurons through mechanosensitive ion channels, leading to reversible calcium signaling and increased c-Fos expression in targeted brain areas. This approach allows for the selective activation of motor cortex regions, evoking limb movements, and the activation of deep brain regions to elicit distinct behaviors such as rotation or freezing. The method also demonstrates therapeutic effects by selectively activating 5-HT neurons in the dorsal raphe nucleus (DRN), reducing depression-like behaviors in mice. PGVs are biocompatible, non-toxic, and do not interfere with normal brain function. The study shows that PGVs can enhance the spatial precision and temporal control of ultrasound neuromodulation, enabling targeted activation of deep brain circuits without genetic modification. The method is safe, with no observed cell damage or inflammation, and has potential applications in treating neurological disorders. The results indicate that PGVs-actuated ultrasound can precisely modulate specific neural circuits, induce distinct behaviors, and rescue neurological conditions. The study highlights the potential of nanobubble-mediated ultrasound as a promising, minimally-invasive approach for targeted neuromodulation.