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。然而，LNP 的医学应用受到其低内体破坏率、高毒性和较长的组织持久性时间的限制。在内体中快速水解的 LNP （RD-LNP） 可以解决限制基于 LNP 的疗法的问题，并显着扩展其应用，但合成一直具有挑战性。在这里，我们提出了一种称为“叠氮基缩醛”的酸降解接头，它可以在几分钟内在内体中水解并能够产生 RD-LNP。由聚乙二醇脂质、阴离子脂质和阳离子脂质组成的酸降解脂质是用叠氮基-缩醛接头合成的，用于生成 RD-LNP，这显着改善了 LNP-mRNA 复合物在体外和体内的性能。总的来说，与传统 LNP 相比，RD-LNP 更有效地将 mRNA 递送到小鼠的肝脏、肺、脾脏和大脑以及体外造血干细胞和祖细胞。这些实验表明，工程化 LNP 体内水解速率在扩展 LNP 的医学应用方面具有巨大潜力。