Tissue-specific mRNA delivery and prime editing with peptide-ionizable lipid nanoparticles

Lipid Nanoparticles for mRNA delivery and Gene Editing have the potential to transform the current therapeutic landscape. Nonetheless, a major bottleneck using this technology is the difficulty in achieving cell- and tissue-specific delivery and avoiding liver accumulation. Here we report the rational design of peptide ionizable Lipids to assemble Lipid Nanoparticles with organ-selective mRNA delivery. Structure-activity and structure-selectivity relationship analyses enable us to obtain a general and predictable strategy for peptide ionizable lipid design. By incorporating artificial ionizable and natural Amino acids and/or Functional Molecules into peptide ionizable Lipids, we create Lipid Nanoparticles with tissue-specific targeting, including the Lungs, liver, spleen, Thymus and bone. In particular, Lipid Nanoparticles containing peptide Lipids targeting the liver show comparable efficacy and safety compared with FDA-approved formulations. Furthermore, Lipid Nanoparticles with peptide Lipids achieve the efficient co-delivery of PEmax mRNA and engineered prime editing guide RNA for prime editing of the liver and Lungs. Overall, our platform offers a predictable methodology for the rational design of tissue-targeting Lipid Nanoparticles that might aid the development of improved mRNA-based Gene Editing therapeutics.