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.

Department of Bioengineering and Cancer Center at Illinois University of Illinois Urbana Champaign Urbana IL USA

Department of Bioengineering and Innovative Genomics Institute University of California Berkeley CA USA

Department of Bioengineering School of Medicine Stanford University Stanford CA USA

Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio San Antonio TX USA

Department of Pathophysiology Faculty of Medicine in Pilsen Charles University Plzen Czech Republic

Department of Science and Environment Roskilde University Roskilde Denmark

Department of Surgery Department of Biomedical Engineering and Institute for Pediatric Regenerative Medicine Shriners Children's University of California Davis Sacramento CA USA

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