4D Brain-Targeting Nanomedicines for Treating Neurodegeneration

Aging, Aging, genetic, and environmental factors have increased the prevalence of patients with neurodegenerative brain conditions, with limited treatment modalities. One prerequisite for effective brain treatments is the ability to target next-generation medications, including RNA and protein drugs, to specific neurons and brain regions. Nanotechnology platforms offer new therapeutic avenues for targeting drugs to organs and cells; their implementation in neurodegenerative diseases is nascent. In this research program, we aim to advance far beyond the state-of-the-art and elucidate the molecular and structural characteristics for designing nanotechnology drugs that target and treat brain neurodegeneration. In preliminary studies, we show that the blood-brain-barrier (BBB) overexpresses disease-specific receptors during neurodegeneration, which enable targeted nanoparticles to cross the BBB and penetrate neurons. Albeit these findings, the magnitude, mechanism, and nanotechnological molecular pattern for brain targeting are lacking. To address this fundamental gap, we will use advanced computation and engineering concepts to develop 4D-brain-targeting nanoparticles, that cross the BBB intact to target specific neuronal populations and brain regions. Robotic synthesis, coupled with active learning algorithms will be used to construct nanoparticles with combinations of targeting moieties on their surface and evaluate their neuronal specificity. Supported microfluidic BBB apparatus will be used to screen the nanoparticles ability to target and cross the BBB. A track-and-seek radar system will locate the nanoparticles in the brain, directing localized robotic biopsy of the nanoparticles in the destination cells in the brain. To connect our findings to future clinical implementation, fMRI will be used to record the therapeutic activity of the nanoparticles in the brain. This program will provide the community with essential findings to allow brain-targeted therapeutics.