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Here, we establish a structure\u2013activity relationship framework for peptide ionizable lipids (PILs) to facilitate the rational design of safe and effective mRNA\u2010LNPs. The PIL structure comprises three modular components: building block, side\u2010chain length, and hydrophobic tail. Through systematic optimization, a lead compound (Dab4) with four building blocks and a moderate side chain length was identified, demonstrating minimized hepatotoxicity while maintaining superior delivery performance. Leveraging this framework, a series of Dab4\u2010derived PILs with three tail types, including alkyl (a\u2010tail), ester (aat\u2010tail), and hydroxyl (e\u2010tail), were synthesized. This tail chemistry determined organ tropism, with B12\u2010a13Dab4 (a\u2010tail) showing optimal performance in the liver. The B12\u2010a13Dab4 LNP exhibited significantly higher hepatic delivery efficiency and markedly improved biosafety compared with the FDA\u2010approved SM\u2010102 formulation. Moreover, B12\u2010a13Dab4 LNP efficiently triggers in vivo prime editing by co\u2010delivering PE7 mRNA and epegRNA, and achieves significant therapeutic effects in a Hereditary Tyrosinemia Type 1 (HT\u20101) model through repeated delivery fumarylacetoacetate hydrolase (FAH) mRNA. This study establishes rational design principles for PILs that strike a balance between efficacy and safety, offering a versatile mRNA\u2010LNP platform for the advancement of gene editing and protein replacement therapies.<\/jats:p>","DOI":"10.1002\/adma.202522552","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T07:04:16Z","timestamp":1770620656000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Optimizing Peptide Ionizable Lipids Enables Efficient and Low\u2010Toxicity mRNA Delivery for In Vivo Prime Editing and Protein Replacement Therapy"],"prefix":"10.1002","volume":"38","author":[{"given":"Qiu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering College of Future Technology Peking University  Beijing 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