Authors
Yi Lin, Mengyao Li, Zijin Luo, Yanan Meng, Yan Zong, Hongyu Ren, Xiaolu Yu, Xiaoqiong Tan, Fan Liu, Tuo Wei, Qiang Cheng
Published in
Nature materials. Sep 01, 2025. Epub Sep 01, 2025.
Abstract
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.
PMID:
40890498
Bibliographic data and abstract were imported from PubMed on 02 Sep 2025.
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