1. Academic Validation
  2. Peptide-Functionalized Lipid Nanoparticles for Targeted Systemic mRNA Delivery to the Brain

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

  • Nano Lett. 2025 Jan 15;25(2):800-810. doi: 10.1021/acs.nanolett.4c05186.
Emily L Han 1 Sophia Tang 1 Dongyoon Kim 1 Amanda M Murray 1 Kelsey L Swingle 1 Alex G Hamilton 1 Kaitlin Mrksich 1 Marshall S Padilla 1 Rohan Palanki 1 2 Jacqueline J Li 1 Michael J Mitchell 1 3 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 2 Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States.
  • 3 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 4 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 5 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 6 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 7 Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Abstract

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 exosome secretion. Finally, we show that LNP peptide functionalization enhances mRNA transfection in the mouse brain and reduces hepatic delivery after systemic administration. Specifically, RVG29 LNPs improved neuronal transfection in vivo, establishing its potential as a nonviral platform for delivering mRNA to the brain.

Keywords

blood-brain barrier; brain delivery; lipid nanoparticles; mRNA; neurons; peptides.

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