Precise antibody delivery to the brain via nanobubble-actuated focused ultrasound alleviates depression

Precise, noninvasive drug delivery to small but important brain regions is challenging and highly desired given the brain's inherent complexity and heterogeneous nature. Here, we report an approach utilizing focused ultrasound (FUS) combined with nanobubbles to successfully navigate this challenge. Compared to traditional microbubbles, nanobubbles exhibit superior acoustic properties. The nanobubbles, when exposed to FUS, induce a highly localized and reversible opening of the blood-brain barrier (BBB) with significantly enhanced precision (up to fourfolds compared to microbubbles, as measured by the precision loss metric). Repeated multitarget FUS-NB precisely delivers macromolecular human-derived anti-N-methyl-D-aspartate receptors monoclonal antibodies (HuMAbs) into the small brain region within a 2-h half-life window per opening. Fluorescence images confirm HuMAb retention in the brain parenchyma for at least 10 d postadministration. With this approach, we targeted the lateral habenula, a small but effective brain target for antidepressant treatments, and significantly alleviated depression-like symptoms at least 2 wk in a mouse model (tail suspension test/forced swim test: P < 0.01/0.05). Moreover, minimal red blood cell extravasation (0.9‱ affected area) was observed in the treated region after multiple FUS treatments, indicating the safety and tolerability of FUS-nanobubble-mediated BBB opening. The enhanced delivery precision, coupled with a favorable safety profile, positions our approach as a promising strategy for antibody therapy with significant clinical translation potential.