Acid-degradable lipid nanoparticles enhance the delivery of mRNA

Sheng Zhao, Kewa Gao, Hesong Han*, Michael Stenzel, Boyan Yin, Hengyue Song, Atip Lawanprasert, Josefine Eilsø Nielsen, Rohit Sharma, Opeyemi H. Arogundade, Sopida Pimcharoen, Yu Ju Chen, Abhik Paul, Jan Tuma, Michael G. Collins, Yofiel Wyle, Matileen Grace Cranick, Benjamin W. Burgstone, Barbara S. Perez, Annelise E. BarronAndrew M. Smith, Hye Young Lee, Aijun Wang*, Niren Murthy*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
JournalNature Nanotechnology
VolumeEarly Access
ISSN1748-3387
DOIs
Publication statusPublished - 2024

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