Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.

Niemann‐Pick disease type C (NPC) is a severe disorder that is characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and sphingolipids. The compound 2‐hydroxypropyl‐β‐cyclodextrin (HPβCD) has high cholesterol complexation capacity and is currently under clinical investigation for the NPC treatment. However, due to its short blood half‐life, high doses are required to produce a therapeutic effect. In this work, stable polymerized HPβCD is generated to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8–312 kDa) display a ninefold greater cholesterol complexation capacity than monomeric HPβCD but are taken up to a lower extent, resulting in an overall comparable in vitro effect. In vivo, the 19.3 kDa HPβCD exhibits a longer half‐life than the monomeric HPβCD but it does not increase the life span of Npc1 mice, possibly due to reduced brain penetration. This is circumvented by the application of magnetic resonance imaging‐guided low intensity‐pulsed focused ultrasound (MRIg‐FUS), which increases the brain penetration of the CD. In conclusion, stable polymerized HPβCDs can elucidate CDs’ mechanism of action while the use of MRIg‐FUS warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the NPC treatment.