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This study aims to develop highly efficient ionizable components that accurately match different targeting lipid systems through the modular design of LPs. Based on this, a lipopeptide\u2010based organ\u2010specific targeting (POST) LNP screening strategy is constructed, in which lysine\u2010histidine\u2010based lipopeptides (KH\u2010LPs) are designed as highly efficient ionizable components. The optimal KH\u2010LP LNP screened in vitro shows excellent siRNA\/mRNA transfecting ability in various hard\u2010to\u2010transfect cell lines. Compared to the classic LNPs, the POST LNPs screened in vivo achieve even higher (or at least comparable) efficiency and specificity in delivering mRNA and siRNA to the lung, liver, and spleen, respectively. The structure\u2010activity relationship (SAR) proves that the modular regulation of LP structures can accurately provide the optimal ionizable components for different targeting lipid systems, demonstrating the potential of this strategy in developing efficient and selective targeting systems, which is expected to open up more possibilities for gene therapy.<\/jats:p>","DOI":"10.1002\/adma.202415643","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T04:50:54Z","timestamp":1739249454000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Modular Design of Lipopeptide\u2010Based Organ\u2010Specific Targeting (POST) Lipid Nanoparticles for Highly Efficient RNA Delivery"],"prefix":"10.1002","volume":"37","author":[{"given":"Chuanmei","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Engineering School of Chemical Engineering and Technology Tianjin University  Tianjin 300072 P. 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