Poster Session 6, 4:15 PM - 5:00 PM: Campus Center Auditorium [A33]

Systematic Screening of Lipid Nanoparticles Surface Properties for Diffusion and Retention in the Brain

Presenter: Vy Do

Faculty Sponsor: Jingjing Gao

School: UMass Amherst

Research Area: Biomedical Engineering

ABSTRACT

Genetic medicine offers tremendous advantages for the treatment of various central nervous system (CNS) diseases by modulating root-cause mechanisms through gene expression regulation. Lipid nanoparticles (LNPs) have been widely employed as delivery vectors for gene therapy due to their low immunogenicity, protection against cargo degradation, and high tunability. While LNPs for brain delivery have been mostly engineered to bypass the blood-brain barrier (BBB), the spatial distribution and cellular tropism of LNPs within the brain parenchyma are also critical factors in determining their translational success. However, how surface physicochemical properties govern interactions between LNPs and the brain environment to determine their residence is poorly understood. In this study, we formulated 65 LNPs with varying surface functional lipids and concentrations and injected them into hippocampal or cortical sites to evaluate their diffusion, retention, and cell-type specificity. Through parallel high-throughput screening, we identified top-performing formulations with distinct spreading and localization capabilities and validated their performance by delivering eGFP mRNA. Our results reveal a panel of LNP formulations with diffusion or retention profiles across brain regions and their preferential uptake by specific brain cell types, allowing for applications in targeted delivery to specific areas or cell populations relevant to neurodegenerative diseases. This study establishes a foundation for further rational development of LNPs with engineered surface characteristics for targeted CNS gene delivery.

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