Peptide-Functionalized Lipid Nanoparticles for Targeted Systemic mRNA Delivery to the Brain
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.
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Cites
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- Authors
- Han, E. L., Tang, S., Kim, D., Murray, A. M., Swingle, K. L., Hamilton, A. G., Mrksich, K., Padilla, M. S., Palanki, R., Li, J. J., & Mitchell, M. J.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Abramson Cancer Center (US)
- Corresponding author
- Mitchell, Michael J.
- ORCID
- Venue
- Nano Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-12-17
- Volume
- 25
- Issue
- 2
- Pages
- 800-810
- ISSN
- 1530-6984 (ISSN-L)
- 1530-6992
- OpenAlex
- W4405493794
- Cited by
- 158
- References
- 7
- Citations by year
- 2026: 94 · 2025: 64
- FWCI
- 21.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nano Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation Graduate Research Fellowship Program (1845298)
- National Heart, Lung, and Blood Institute (F30HL16246501A1)
- National Institute of Dental and Craniofacial Research (T90DE030854)
- American Cancer Society (RSG-22-122-01-ET)
- Division of Chemical, Bioengineering, Environmental, and Transport Systems (2145491)
- Burroughs Wellcome Fund
- National Institutes of Health (DP2 TR002776)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- lipid nanoparticles, mRNA delivery, brain targeting, blood-brain barrier, peptide functionalization, T7 peptide, brain endothelial cells, neuronal transfection, endothelial transcytosis, exosome secretion, serum protein adsorption, intracellular trafficking, hepatic accumulation, non-viral gene delivery, systemic drug delivery
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Humans, Lipids, Liposomes, Neurons, Peptides, RNA, Messenger, Transfection, Endothelial Cells, Mice, Nanoparticles
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