TY - JOUR
T1 - Fusogenic Coiled-Coil Peptides Enhance Lipid Nanoparticle-Mediated mRNA Delivery upon Intramyocardial Administration
AU - Zeng, Ye
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
N1 - Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society
PY - 2023/12/12
Y1 - 2023/12/12
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.
AB - 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.
KW - fusogenic coiled-coil
KW - intramyocardial delivery
KW - iPSC-CM
KW - lipid nanoparticles
KW - mRNA delivery
UR - http://www.scopus.com/inward/record.url?scp=85179151370&partnerID=8YFLogxK
U2 - 10.1021/acsnano.3c05341
DO - 10.1021/acsnano.3c05341
M3 - Article
C2 - 37982378
AN - SCOPUS:85179151370
SN - 1936-0851
VL - 17
SP - 23466
EP - 23477
JO - ACS Nano
JF - ACS Nano
IS - 23
ER -