CAREER: Advancing Precision Biomimetic Nanodelivery for Neurovascular Inflammation

Inflammation of the brain plays a major role in diseases such as stroke and dementia. Delivering medicines to the brain is difficult because often they do not reach damaged brain tissues. This CAREER project will produce biomimetic nanoparticles that have molecules specifically targeting brain blood vessels. The project will determine how the nanoparticles adhere to and cross inflamed brain blood vessels in disease-mimicking models. The project will integrate nanotechnology, bioengineering, vascular biology, and neuroscience to find how engineered biomimetic nanoparticles interact with disease microenvironments. Results will suggest new strategies for precision nanomedicine. The project will support undergraduate research opportunities. It will also develop biomaterials learning modules and podcasts to communicate bioengineering advances to a broad audience. Cerebrovascular inflammation drives and amplifies neurological disorders. However, an activated brain vascular endothelium and a compromised blood-brain barrier present opportunities for targeted therapeutic delivery. This CAREER research project will leverage multivalent interactions between surface-modified biomimetic nanoparticles and inflammatory vascular receptors to achieve precise delivery to cerebrovascular lesion sites. The project will build on a monocyte membrane-cloaked nanoparticle platform that exploits natural monocyte adhesion mechanisms to target inflamed endothelial linings. These monocyte-mimetic nanoparticles will be engineered to surface-display a brain-vasculature-targeting peptide that binds to a receptor highly expressed at the blood-brain barrier. The research objectives are to: 1) Engineer surface ligand display on monocyte-mimetic nanoparticles and determine binding mechanisms across distinct endothelial beds; 2) Model the targeting, adhesion, and transport of surface-modified monocyte-mimetic nanoparticles using a three-dimensional inflamed brain microvascular network-on-a-chip; and 3) Evaluate targeting specificity, delivery efficacy, and blood interaction profiles of surface-modified monocyte-mimetic nanoparticles in a mouse model of cerebrovascular disease. Findings from this project will establish design principles governing how surface-engineered biomimetic nanocarriers interact with inflamed cerebrovascular interfaces, advancing fundamental understanding of neurovascular inflammation-dependent nanoparticle transport in complex biological environments. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.