<p>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.</p>