PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake
Open accessAbstract
Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.
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Coupling pulmonary affinity ligands to nanoparticles can significantly increase mRNA delivery to the lungs.
“For example, coupling pulmonary affinity ligands to nanoparticles can significantly increase mRNA delivery to the lungs.[42]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [42]
Relative to non-targeted LNPs, systemic administration of PECAM-1 coupled mRNA LNPs exhibited approximately 200-fold inhibition and 25-fold elevation of luciferase expression in the liver and lungs, respectively.
“Relative to non-targeted LNPs, systemic administration of PECAM-1 coupled mRNA LNPs exhibited approximately 200-fold inhibition and 25-fold elevation of luciferase expression in the liver and the lungs, respectively.[42]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [42]
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“The same group targeted lung and inflamed brain endothelial cells using anti-PECAM-1 (95) and -VCAM (96) antibodies conjugated to iLNPs and cLNPs respectively.”
Background
- Authors
- Parhiz, H., Shuvaev, V. V., Pardi, N., Khoshnejad, M., Kiseleva, R. Y., Brenner, J. S., Uhler, T., Tuyishime, S., Mui, B. L., Tam, Y. K., Madden, T. D., Hope, M. J., Weissman, D., & Muzykantov, V. R.
- Affiliations
- University of Pennsylvania (US)
- Acuitas Therapeutics (Canada) (CA)
- Corresponding author
- Parhiz, Hamideh
- Weissman, Drew
- Muzykantov, Vladimir R.
- ORCID
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 291
- Pages
- 106-115
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC6477695
- OpenAlex
- W2897789147
- Cited by
- 233
- References
- 40
- Citations by year
- 2026: 46 · 2025: 46 · 2024: 46 · 2023: 35 · 2022: 24 · 2021: 15 · 2020: 16 · 2019: 5
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (RO1 HL128392, T32 HL007915)
- National Institute of Allergy and Infectious Diseases (R01-AI084860, R01-AI124429)
- amfAR, The Foundation for AIDS Research
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- CD31, lipid nanoparticle mRNA delivery, vascular targeting, nucleoside-modified mRNA
- MeSH terms
- Animals, Apolipoproteins E, Cell Line, Drug Carriers, Endothelium, Vascular, Humans, Mice, Inbred C57BL, RNA, Messenger, Tissue Distribution, Drug Delivery Systems, Immunoconjugates, Platelet Endothelial Cell Adhesion Molecule-1, Nanoparticles, Human Umbilical Vein Endothelial Cells, Administration, Intravenous
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