Ultrasound-sensitive nanodroplets achieve targeted neuromodulation.

Abstract Focused ultrasound (FUS) offers an attractive tool for non-invasive neuromodulation, addressing a clinical need to develop more minimally invasive approaches that are safer, more tolerable and versatile. In combination with a cavitation agent, the effects of ultrasound can be amplified and localized for therapy. Using c-Fos expression mapping, we show how ultrasound-sensitive nanodroplets can be used to induce either neurosuppression or neurostimulation, without disrupting the blood-brain barrier in rats. By repurposing a commercial ultrasound contrast agent, Definity, lipid-shell decafluorobutane-core nanodroplets of 212.5 ± 2.0 nm were fabricated and loaded with or without pentobarbital. FUS was delivered with an atlas-based targeting system at 1.66 MHz to the motor cortex of rats, using a feedback-controller to detect successful nanodroplet vaporization and drug release. Neuromodulation was quantified through changes in sensorimotor function and c-Fos expression. Following FUS-triggered delivery, sham nanodroplets induced a 22.6 ± 21% increase in local c-Fos expression, whereas pentobarbital-loaded nanodroplets induced a 21.7 ± 13% decrease (n = 6). Nanodroplets, combined with FUS, offer an adaptable tool for neuromodulation, through local delivery of small molecule anesthetics or targeted mechanical effects.