TY - JOUR
T1 - Acid-degradable lipid nanoparticles enhance the delivery of mRNA
AU - Zhao, Sheng
AU - Gao, Kewa
AU - Han, Hesong
AU - Stenzel, Michael
AU - Yin, Boyan
AU - Song, Hengyue
AU - Lawanprasert, Atip
AU - Nielsen, Josefine Eilsø
AU - Sharma, Rohit
AU - Arogundade, Opeyemi H.
AU - Pimcharoen, Sopida
AU - Chen, Yu Ju
AU - Paul, Abhik
AU - Tuma, Jan
AU - Collins, Michael G.
AU - Wyle, Yofiel
AU - Cranick, Matileen Grace
AU - Burgstone, Benjamin W.
AU - Perez, Barbara S.
AU - Barron, Annelise E.
AU - Smith, Andrew M.
AU - Lee, Hye Young
AU - Wang, Aijun
AU - Murthy, Niren
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/11
Y1 - 2024/11
N2 - Lipid nanoparticle (LNP)–mRNA complexes are transforming medicine. However, the medical applications of LNPs are limited by their low endosomal disruption rates, high toxicity and long tissue persistence times. LNPs that rapidly hydrolyse in endosomes (RD-LNPs) could solve the problems limiting LNP-based therapeutics and dramatically expand their applications but have been challenging to synthesize. Here we present an acid-degradable linker termed ‘azido-acetal’ that hydrolyses in endosomes within minutes and enables the production of RD-LNPs. Acid-degradable lipids composed of polyethylene glycol lipids, anionic lipids and cationic lipids were synthesized with the azido-acetal linker and used to generate RD-LNPs, which significantly improved the performance of LNP–mRNA complexes in vitro and in vivo. Collectively, RD-LNPs delivered mRNA more efficiently to the liver, lung, spleen and brains of mice and to haematopoietic stem and progenitor cells in vitro than conventional LNPs. These experiments demonstrate that engineering LNP hydrolysis rates in vivo has great potential for expanding the medical applications of LNPs.
AB - Lipid nanoparticle (LNP)–mRNA complexes are transforming medicine. However, the medical applications of LNPs are limited by their low endosomal disruption rates, high toxicity and long tissue persistence times. LNPs that rapidly hydrolyse in endosomes (RD-LNPs) could solve the problems limiting LNP-based therapeutics and dramatically expand their applications but have been challenging to synthesize. Here we present an acid-degradable linker termed ‘azido-acetal’ that hydrolyses in endosomes within minutes and enables the production of RD-LNPs. Acid-degradable lipids composed of polyethylene glycol lipids, anionic lipids and cationic lipids were synthesized with the azido-acetal linker and used to generate RD-LNPs, which significantly improved the performance of LNP–mRNA complexes in vitro and in vivo. Collectively, RD-LNPs delivered mRNA more efficiently to the liver, lung, spleen and brains of mice and to haematopoietic stem and progenitor cells in vitro than conventional LNPs. These experiments demonstrate that engineering LNP hydrolysis rates in vivo has great potential for expanding the medical applications of LNPs.
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UR - http://www.scopus.com/inward/citedby.url?scp=85201940309&partnerID=8YFLogxK
U2 - 10.1038/s41565-024-01765-4
DO - 10.1038/s41565-024-01765-4
M3 - Article
C2 - 39179796
AN - SCOPUS:85201940309
SN - 1748-3387
VL - 19
SP - 1702
EP - 1711
JO - Nature Nanotechnology
JF - Nature Nanotechnology
IS - 11
ER -