Fusogenic Coiled-Coil Peptides Enhance Lipid Nanoparticle-Mediated mRNA Delivery upon Intramyocardial Administration

Ye Zeng; Mariona Estapé Senti; M. Clara I. Labonia; Panagiota Papadopoulou; Maike A.D. Brans; Inge Dokter; Marcel H. Fens; Alain van Mil; Joost P.G. Sluijter; Raymond M. Schiffelers; Pieter Vader; Alexander Kros

doi:10.1021/acsnano.3c05341

Fusogenic Coiled-Coil Peptides Enhance Lipid Nanoparticle-Mediated mRNA Delivery upon Intramyocardial Administration

Ye Zeng, Mariona Estapé Senti, M. Clara I. Labonia, Panagiota Papadopoulou, Maike A.D. Brans, Inge Dokter, Marcel H. Fens, Alain van Mil, Joost P.G. Sluijter, Raymond M. Schiffelers, Pieter Vader^*, Alexander Kros^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Heart failure is a serious condition that results from the extensive loss of specialized cardiac muscle cells called cardiomyocytes (CMs), typically caused by myocardial infarction (MI). Messenger RNA (mRNA) therapeutics are emerging as a very promising gene medicine for regenerative cardiac therapy. To date, lipid nanoparticles (LNPs) represent the most clinically advanced mRNA delivery platform. Yet, their delivery efficiency has been limited by their endosomal entrapment after endocytosis. Previously, we demonstrated that a pair of complementary coiled-coil peptides (CPE4/CPK4) triggered efficient fusion between liposomes and cells, bypassing endosomal entrapment and resulting in efficient drug delivery. Here, we modified mRNA-LNPs with the fusogenic coiled-coil peptides and demonstrated efficient mRNA delivery to difficult-to-transfect induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs). As proof of in vivo applicability of these fusogenic LNPs, local administration via intramyocardial injection led to significantly enhanced mRNA delivery and concomitant protein expression. This represents the successful application of the fusogenic coiled-coil peptides to improve mRNA-LNPs transfection in the heart and provides the potential for the advanced development of effective regenerative therapies for heart failure.

Original language	English
Pages (from-to)	23466-23477
Number of pages	12
Journal	ACS Nano
Volume	17
Issue number	23
DOIs	https://doi.org/10.1021/acsnano.3c05341
Publication status	Published - 12 Dec 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society

Funding

We acknowledge the financial support of the Dutch Research Council (NWO) via an XS grant to A.K. This work was supported by the EXPERT project, which has received Funding from the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 825828 (M.E.S, R.M.S). P.V. acknowledges support from the Dutch Heart Foundation (Dr. E. Dekker Senior Scientist grant, no. 2019T049).

Funders	Funder number
Horizon 2020 Framework Programme	825828
Hartstichting	2019T049
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

fusogenic coiled-coil
intramyocardial delivery
iPSC-CM
lipid nanoparticles
mRNA delivery

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10.1021/acsnano.3c05341Licence: CC BY

zeng-et-al-2023-fusogenic-coiled-coil-peptides-enhance-lipid-nanoparticle-mediated-mrna-delivery-upon-intramyocardialFinal published version, 7.43 MBLicence: CC BY

Cite this

Zeng, Y., Estapé Senti, M., Labonia, M. C. I., Papadopoulou, P., Brans, M. A. D., Dokter, I., Fens, M. H., van Mil, A., Sluijter, J. P. G., Schiffelers, R. M., Vader, P., & Kros, A. (2023). Fusogenic Coiled-Coil Peptides Enhance Lipid Nanoparticle-Mediated mRNA Delivery upon Intramyocardial Administration. ACS Nano, 17(23), 23466-23477. https://doi.org/10.1021/acsnano.3c05341

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abstract = "Heart failure is a serious condition that results from the extensive loss of specialized cardiac muscle cells called cardiomyocytes (CMs), typically caused by myocardial infarction (MI). Messenger RNA (mRNA) therapeutics are emerging as a very promising gene medicine for regenerative cardiac therapy. To date, lipid nanoparticles (LNPs) represent the most clinically advanced mRNA delivery platform. Yet, their delivery efficiency has been limited by their endosomal entrapment after endocytosis. Previously, we demonstrated that a pair of complementary coiled-coil peptides (CPE4/CPK4) triggered efficient fusion between liposomes and cells, bypassing endosomal entrapment and resulting in efficient drug delivery. Here, we modified mRNA-LNPs with the fusogenic coiled-coil peptides and demonstrated efficient mRNA delivery to difficult-to-transfect induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs). As proof of in vivo applicability of these fusogenic LNPs, local administration via intramyocardial injection led to significantly enhanced mRNA delivery and concomitant protein expression. This represents the successful application of the fusogenic coiled-coil peptides to improve mRNA-LNPs transfection in the heart and provides the potential for the advanced development of effective regenerative therapies for heart failure.",

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AU - Estapé Senti, Mariona

AU - Labonia, M. Clara I.

AU - Papadopoulou, Panagiota

AU - Brans, Maike A.D.

AU - Dokter, Inge

AU - Fens, Marcel H.

AU - van Mil, Alain

AU - Sluijter, Joost P.G.

AU - Schiffelers, Raymond M.

AU - Vader, Pieter

AU - Kros, Alexander

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N2 - Heart failure is a serious condition that results from the extensive loss of specialized cardiac muscle cells called cardiomyocytes (CMs), typically caused by myocardial infarction (MI). Messenger RNA (mRNA) therapeutics are emerging as a very promising gene medicine for regenerative cardiac therapy. To date, lipid nanoparticles (LNPs) represent the most clinically advanced mRNA delivery platform. Yet, their delivery efficiency has been limited by their endosomal entrapment after endocytosis. Previously, we demonstrated that a pair of complementary coiled-coil peptides (CPE4/CPK4) triggered efficient fusion between liposomes and cells, bypassing endosomal entrapment and resulting in efficient drug delivery. Here, we modified mRNA-LNPs with the fusogenic coiled-coil peptides and demonstrated efficient mRNA delivery to difficult-to-transfect induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs). As proof of in vivo applicability of these fusogenic LNPs, local administration via intramyocardial injection led to significantly enhanced mRNA delivery and concomitant protein expression. This represents the successful application of the fusogenic coiled-coil peptides to improve mRNA-LNPs transfection in the heart and provides the potential for the advanced development of effective regenerative therapies for heart failure.

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Fusogenic Coiled-Coil Peptides Enhance Lipid Nanoparticle-Mediated mRNA Delivery upon Intramyocardial Administration

Abstract

Bibliographical note

Funding

Keywords

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