With recent advancement in transcranial focused ultrasound (FUS) technology, non-invasive and targeted BBB opening became possible in several animal models5,6. This technique involves a systemic injection of a mixture composed of ultrasound contrast agents (lipid-based microbubbles) and molecules to be delivered.

The emitted ultrasonic waves propagate through the skull and cause the microbubbles to cavitate (to oscillate) within the capillaries in the targeted brain region7,8. It was reported that this interaction transiently loosens the tight junctions between endothelial cells9. As a result, the BBB is temporarily opened and the molecules of interest diffuse into the brain parenchyma according to their concentration gradient10. By taking the advantage of the non-invasive nature of the FUS technique, we report here the design and implementation of a FUS-facilitated gene delivery for optogenetic applications. Viral vectors encoding various light-activated protein channels delivered via this approach allow for an entirely non-invasive neural stimulation procedure in vivo.