Holographic focused ultrasound enables multitarget EV and MSC delivery for neurovascular repair after ischemic stroke

Noninvasive multitarget delivery of size-diverse therapeutics, including extracellular vesicles (EVs) and mesenchymal stromal cells (MSCs), to peri-infarct zones is hindered by the blood-brain barrier (BBB) and heterogeneous infarct topographies. Here, we developed a hologram-assisted multitarget BBB opening (HaMBO) platform combining low-cost 3D-printed holograms with a single-element ultrasound transducer. Spatially tailored acoustic fields enabled localized BBB opening along infarct borders. In male mice with transient focal cerebral ischemia, a single two-minute HaMBO treatment safely enhanced the peri-infarct delivery of EVs and MSCs, reduced brain atrophy by ~56%, increased angiogenesis by ~2-fold and neural progenitor proliferation by ~4-fold, and improved long-term behavioral recovery. Spatial transcriptomic analysis associated HaMBO-assisted EV therapy with reduced macrophage infiltration and enhanced pro-angiogenic and neurogenic signaling. Human skull-based simulations further demonstrated HaMBO’s clinical adaptability across diverse stroke scenarios. Thus, HaMBO provides a safe, low-cost, and customizable platform for noninvasive multitarget delivery in ischemic stroke and other neurological disorders. Noninvasive multitarget delivery to peri-infarct regions after ischemic stroke remains challenging. Here, authors use holographic focused ultrasound to deliver EVs and MSCs to infarct borders, promoting neurovascular repair in mice.