Site-Specific Brain Therapeutics

Identifying the correct brain target for therapeutic intervention remains a central challenge in neurology and neurosurgery. How can we determine whether modulating a specific brain region will benefit a patient before committing to an invasive procedure? Our work addresses this challenge by developing noninvasive, site-specific technologies that enable precise modulation of targeted brain regions and evaluation of their therapeutic potential.

    To this end, we developed Regionally Activated Interstitial Drugs (RAID), a noninvasive, non-genetic platform for site- and molecularly specific neuromodulation in the intact brain. RAID leverages focused ultrasound–mediated blood-brain barrier opening (FUS-BBBO) to deliver engineered enzymes to targeted regions, where they remain for several days and locally convert systemically administered, BBB-permeable prodrugs into active neuropharmacological agents. This approach enables sustained, localized modulation of neuronal activity following a single treatment. Importantly, RAID is highly versatile and can be adapted to different enzyme–prodrug pairs, providing a generalizable framework for controlling diverse aspects of central nervous system function.

    Building on this principle of site-specific activation, we are developing SIGNET (Site-specific, Ultrasound-Guided Neuropeptides), a platform for noninvasive, programmable, and localized activation of neuropeptides. SIGNET enables precise modulation of neural circuits through controlled release of peptide-based signals, expanding neuromodulation beyond small molecules.

    In parallel, we are advancing SONAR (Site-specific, Noninvasive, RNA-guided Cell-fate Regulation), an RNA-guided, focused ultrasound–enabled platform for treating brain tumors. SONAR is designed to selectively eliminate disease-driving mutant cells through molecularly precise recognition and spatiotemporal control, offering a targeted strategy for treating tumors such as diffuse midline glioma while sparing healthy tissue.

    Finally, we are developing programmable, ultrasound-leveraged, site-specific exosome platforms for drug delivery without the need for blood-brain barrier opening. This approach enables noninvasive, repeatable, and spatially precise delivery of therapeutics using engineered exosomes, further expanding the toolkit for targeted intervention in the brain.

    Together, these technologies establish a unified framework for noninvasive, site-specific control of brain function, enabling precise and targeted disease treatment, with broad implications for both fundamental neuroscience and clinical translation.