Nature nanotechnology · 2024
Acid-degradable lipid nanoparticles enhance the delivery of mRNA.
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Zhao Sheng, Gao Kewa, Han Hesong, Stenzel Michael, Yin Boyan, Song Hengyue, Lawanprasert Atip, Nielsen Josefine Eilsø, Sharma Rohit, Arogundade Opeyemi H, Pimcharoen Sopida, Chen Yu-Ju, Paul Abhik, Tuma Jan, Collins Michael G, Wyle Yofiel, Cranick Matileen Grace, Burgstone Benjamin W, Perez Barbara S, Barron Annelise E, Smith Andrew M, Lee Hye Young, Wang Aijun, Murthy Niren
Аннотация
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.