Cited by 113RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryTissue Engineering and Regenerative Medicine

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Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles

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Evers, Martijn J.W., Du, Wenjuan, Yang, Qiangbing, Kooijmans, Sander A.A., Vink, Aryan, van Steenbergen, Mies, Vader, Pieter, de Jager, Saskia C.A., Fuchs, Sabine A., Mastrobattista, Enrico, Sluijter, Joost P.G., Lei, Zhiyong, Schiffelers, Raymond·2022·Journal of Controlled Release

DOI 10.1016/j.jconrel.2022.01.027

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Abstract

Lipid Nanoparticles (LNPs) are a promising drug delivery vehicle for clinical siRNA delivery. Modified mRNA (modRNA) has recently gained great attention as a therapeutic molecule in cardiac regeneration. However, for mRNA to be functional, it must first reach the diseased myocardium, enter the target cell, escape from the endosomal compartment into the cytosol and be translated into a functional protein. However, it is unknown if LNPs can effectively deliver mRNA, which is much larger than siRNA, to the ischemic myocardium. Here, we evaluated the ability of LNPs to deliver mRNA to the myocardium upon ischemia-reperfusion injury functionally. By exploring the bio-distribution of fluorescently labeled LNPs, we observed that, upon reperfusion, LNPs accumulated in the infarct area of the heart. Subsequently, the functional delivery of modRNA was evaluated by the administration of firefly luciferase encoding modRNA. Concomitantly, a significant increase in firefly luciferase expression was observed in the heart upon myocardial reperfusion when compared to sham-operated animals. To characterize the targeted cells within the myocardium, we injected LNPs loaded with Cre modRNA into Cre-reporter mice. Upon LNP infusion, Tdtomato+ cells, derived from Cre mediated recombination, were observed in the infarct region as well as the epicardial layer upon LNP infusion. Within the infarct area, most targeted cells were cardiac fibroblasts but also some cardiomyocytes and macrophages were found. Although the expression levels were low compared to LNP-modRNA delivery into the liver, our data show the ability of LNPs to functionally deliver modRNA therapeutics to the damaged myocardium, which holds great promise for modRNA-based cardiac therapies.

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Authors: Evers, M. J. W., Du, W., Yang, Q., Kooijmans, S. A. A., Vink, A., van Steenbergen, M., Vader, P., de Jager, S. C. A., Fuchs, S. A., Mastrobattista, E., Sluijter, J. P. G., Lei, Z., & Schiffelers, R.
Affiliations: University Medical Center Utrecht (NL)
Harbin Medical University (CN)
Utrecht University (NL)
Corresponding author: Schiffelers, Raymond
ORCID: Evers, Martijn J.W.
Yang, Qiangbing
Kooijmans, Sander A.A.
Vink, Aryan
Vader, Pieter
Fuchs, Sabine A.
Mastrobattista, Enrico
Sluijter, Joost P.G.
Lei, Zhiyong
Schiffelers, Raymond
Venue: Journal of Controlled Release
Publisher: Elsevier BV
Published: 2022-03
Volume: 343
Pages: 207-216
ISSN: 0168-3659 (ISSN-L)
DOI: 10.1016/j.jconrel.2022.01.027
OpenAlex: W4206915884
Cited by: 113
References: 48
Citations by year: 2026: 19 · 2025: 44 · 2024: 23 · 2023: 20 · 2022: 7
FWCI: 7.67
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Journal of Controlled Release (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders: European Commission (HORIZON2020, 721058, 725229, 825828)
ZonMw (725229, 116002016)
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (16169)
Ministerie van Economische Zaken, Landbouw en Innovatie
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 › Surgery › Tissue Engineering and Regenerative Medicine
Keywords: lipid nanoparticles, modified mRNA, myocardial ischemia-reperfusion injury, cardiac regeneration, systemic drug delivery, firefly luciferase reporter, Cre reporter mice, cardiac fibroblasts
MeSH terms: Animals, Infarction, Liposomes, Myocardium, RNA, Messenger, RNA, Small Interfering, Luciferases, Firefly, Mice, Nanoparticles

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Delivery of modified mRNA to damaged myocardium by systemic administration of lipid nanoparticles

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