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 - Funding Information:
N.M. thanks the California Institute for Regenerative Medicine (CIRM) DISC2-14045, and the NIH for NIAID award number UM1AI164559, co-funded by NHLBI, NIMH, NIDA, NIDDK and NINDS. N.M. also thanks NIH grants UG3NS115599, R33 and R61DA048444-01, R01MH125979-01, funding from the BAKAR Spark award, the Cystic Fibrosis Foundation, the Innovative Genomics Institute, the CRISPR Cures for Cancer Initiative and the Heritage Medical Research Institute. Cryo-TEM data were collected at the Cal-Cryo facility at the University of California, Berkeley Institute for Quantitative Biosciences (QB3). A.E.B. thanks the NIH for funding this work with a Pioneer Award, grant number 1DP1OD029517-01 and J. J. Truchard and the Truchard Foundation. J.E.N. was funded by grant NNF21OC0068675 from the Novo Nordisk Foundation and the Stanford Bio-X Program. A.W. thanks the NIH grant with number 1R21NS133881-01, California Institute for Regenerative Medicine (CIRM) DISC2-14097, Shriners Children\u2019s basic research award 85400-NCA-24. We thank SLAC for SAXS beamtime, and T. Weiss for support during the SAXS experiment. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH, National Institute of General Medical Sciences (P30GM133894). We also thank the Doudna laboratory for help with the HSPCs transfection experiments.
Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024
Y1 - 2024
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.
U2 - 10.1038/s41565-024-01765-4
DO - 10.1038/s41565-024-01765-4
M3 - Journal article
AN - SCOPUS:85201940309
SN - 1748-3387
VL - Early Access
JO - Nature Nanotechnology
JF - Nature Nanotechnology
ER -