Lipid nanoparticle (LNP)–mRNA complexes are transforming medicine. However, the medical applications of LNPs are limited by their low endosomal disruption rates. LNPs that rapidly hydrolyse in endosomes (RD-LNPs) could solve the problem limiting LNP-based therapeutics and dramatically expand their applications but have been challenging to synthesize. Our lab develops 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. They improve delivery across multiple organs, including liver, lung, spleen, and brain. They also enable efficient delivery to hematopoietic stem and progenitor cells.
