Localized brain delivery of drugs via focused ultrasound-responsive bi-layer nanobubbles

Focused ultrasound (FUS) in combination with micro- or nanobubbles is a promising strategy for transiently and non-invasively opening the blood-brain barrier (BBB) to enable targeted drug delivery to the brain. Here, we report a FUS-responsive delivery system using bi-layer nanobubbles (NBs) loaded with small molecules for enhanced, focused transport into brain tissue. We characterized NBs formulated with different core gases (N 2 , O 2 , SF 6 ) and compared their acoustic cavitation behavior with standard microbubbles (SonoVue). SF 6 NBs demonstrated significantly lower inertial cavitation and ultraharmonic emissions at 0.4 MPa, indicating greater stability and a potentially improved safety profile for BBB disruption. In vitro, small-molecule-loaded NBs achieved an eightfold increase in curcumin delivery to neuronal cells under FUS, compared to free drug. Higher FUS pulse intensities increased cellular uptake and calcium influx but did not induce significant neurotoxicity on their own. In a mouse model, FUS exposure facilitated the penetration of curcumin-loaded NBs across the BBB, achieving localized delivery in the brain. Our results underscore that optimized FUS parameters (1.5 MHz, 0.2–1.2 MPa) can safely enhance BBB permeability in the presence of stable NBs, improving drug delivery efficacy while minimizing tissue damage. These findings align with recent advances in FUS-mediated BBB opening.