NIH grant: Programmable Ultrasound-Leveraged Site-specific Exosomes (1R21EB039194-01)

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NIH grant 1R21EB039194-01: Programmable Ultrasound-Leveraged Site-specific Exosomes
Institute: {'code': 'EB', 'abbreviation': 'NIBIB', 'name': 'National Institute of Biomedical Imaging and Bioengineering', 'admin_org_id': '12500035', 'admin_funding_url': ''}. PI: Zhimin  Huang. Award: $235550.
Start: 2026-08-01T00:00:00.
Programmable Ultrasound-Leveraged Site-specific Exosomes
Project Summary/Abstract:
Precise spatial and temporal control of therapeutic delivery remains a critical challenge in treating neurological
disorders, as conventional systemic drugs often lack regional specificity and cause off-target effects. To address
this, the Principal Investigator recently developed Regionally Activated Interstitial Drugs (RAID), a site-specific
brain therapeutics platform that enables noninvasive modulation of defined brain regions using small-molecule
drugs. RAID employs focused ultrasound (FUS) to transiently open the blood-brain barrier (FUS-BBBO),
delivering enzymes that convert systemically administered prodrugs into active compounds within targeted brain
areas. This approach sustains therapeutic effects for several days after the BBB has reclosed. However,
challenges remain, including potential long-term complications from repetitive BBB opening, should RAID be
used for chronic therapy.
 This proposal presents an innovative strategy that retains spatial precision while eliminating the need for
BBB disruption. We leverage engineered exosomes—biocompatible extracellular vesicles capable of crossing
physiological barriers—as delivery vehicles. To prevent nonspecific uptake during systemic circulation, exosome
surface proteins will be reversibly masked by fusion to albumin-binding domains (ABD) via a TEV (Tobacco etch
virus) protease–cleavable linker. Spatially confined TEV protease expression will be induced in targeted brain
vasculature by low-intensity FUS, enabling localized exosome unmasking and selective payload delivery without
compromising BBB integrity.
 To demonstrate feasibility, we propose two specific aims. First, we will engineer ABD-masked, GFP
(green fluorescent protein)-labeled exosomes and use FUS to induce localized TEV protease expression in brain
endothelial cells, enabling and evaluating site-specific exosome uptake and delivery to adjacent brain tissue.
Second, we will develop a programmable system using AAV (Adeno-associated virus) vectors to achieve FUS-
inducible, heat-activated Cre expression and temporally controlled TEV protease production, allowing repeatable
and sustained exosome delivery to targeted brain regions.
 If successful, this project will establish a transformative platform for programmable, spatiotemporally
controlled, and noninvasive therapeutic delivery to the brain. By integrating molecular masking with FUS-
triggered exosome unmasking, this strategy offers a broadly applicable solution for the chronic treatment of
neurological and other diseases requiring localized drug delivery—advancing the development of safer and more
effective therapies.

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