Peptide-Functionalized Lipid Nanoparticles for Targeted Systemic mRNA Delivery to the Brain

Systemic delivery of large nucleic acids, such as mRNA, to the brain remains challenging in part due to the blood-brain barrier (BBB) and the tendency of delivery vehicles to accumulate in the liver. Here, we design a peptide-functionalized lipid nanoparticle (LNP) platform for targeted mRNA delivery to the brain. We utilize click chemistry to functionalize LNPs with peptides that target receptors overexpressed on brain endothelial cells and neurons, namely the RVG29, T7, AP2, and mApoE peptides. We evaluate the effect of LNP targeting on brain endothelial and neuronal cell transfection in vitro, investigating factors such as serum protein adsorption, intracellular trafficking, endothelial transcytosis, and…

• AC
  American Cancer Society

  Award: RSG-22-122-01-ET
• BW
  Burroughs Wellcome Fund
• NI
  National Institutes of Health

  Award: DP2 TR002776
• NH
  National Heart, Lung, and Blood Institute

  Award: F30HL16246501A1
• NI
  National Institute of Dental and Craniofacial Research

  Award: T90DE030854
• DO
  Division of Chemical, Bioengineering, Environmental, and Transport Systems

  Award: 2145491
• NS
  National Science Foundation Graduate Research Fellowship Program

  Award: 1845298