Department of Bioengineering and Innovative Genomics Institute, University of California, Berkeley, CA, USA.
Department of Surgery, Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine/Shriners Children's, University of California, Davis, Sacramento, CA, USA.
Nat Nanotechnol. 2024 Nov;19(11):1702-1711. doi: 10.1038/s41565-024-01765-4. Epub 2024 Aug 23.
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.
脂质纳米颗粒（LNP）-mRNA 复合物正在改变医学领域。然而，LNP 的医学应用受到其低内体破坏率、高毒性和长时间组织滞留的限制。能够在内涵体中快速水解的 LNPs（RD-LNPs）可以解决限制 LNP 疗法的问题，并极大地扩展其应用范围，但合成起来具有挑战性。在这里，我们提出了一种称为“叠氮缩醛”的酸可降解连接体，它可以在数分钟内在内涵体中水解，并能够生产 RD-LNPs。使用叠氮缩醛连接体合成了由聚乙二醇脂质、阴离子脂质和阳离子脂质组成的酸可降解脂质，并用于生成 RD-LNPs，这显著提高了 LNP-mRNA 复合物在体外和体内的性能。总的来说，RD-LNPs 比传统的 LNPs 更有效地将 mRNA 递送到小鼠的肝脏、肺、脾脏和大脑以及体外的造血干细胞和祖细胞中。这些实验表明，在体内工程化 LNP 水解速率具有极大的潜力来扩展 LNPs 的医学应用。
