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 的医学应用因其内体破坏率低、毒性高和组织持久时间长而受到限制。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”的可酸降解连接体，它可以在几分钟内在内体中水解并能够产生 RD-LNP。用叠氮基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可酸降解脂质，并用于生成RD-LNP，显着改善了LNP-mRNA复合物的体外和体内性能。总的来说，与传统的 LNP 相比，RD-LNP 能够更有效地将 mRNA 递送至小鼠的肝脏、肺、脾和大脑，以及体外递送至造血干细胞和祖细胞。这些实验表明，改造 LNP 体内水解速率对于扩大 LNP 的医学应用具有巨大潜力。