Modular Design of Lipopeptide‐Based Organ‐Specific Targeting (POST) Lipid Nanoparticles for Highly Efficient RNA Delivery

• DOI: 10.1002/adma.202415643
• Publication Date: 2025-02-11T09:50:54Z
• Authors: Chuanmei Tang; Yexi Zhang; Bowen Li; Xiangwei Fan; Zixuan Wang; Rongxin Su; Wei Qi; Yuefei Wang
• Keywords: Lipopeptide

Lipid nanoparticles (LNPs) with highly efficient and specific extrahepatic targeting abilities are promising in gene delivery, the lipopeptides (LPs) excellent designability functionality expected to empower construction of functional LNPs. This study aims develop ionizable components that accurately match different lipid systems through modular design LPs. Based on this, a lipopeptide-based organ-specific (POST) LNP screening strategy is constructed, which lysine-histidine-based (KH-LPs) designed as components. The optimal KH-LP screened vitro shows siRNA/mRNA transfecting ability various hard-to-transfect cell lines. Compared classic LNPs, POST LNPs vivo achieve even higher (or at least comparable) efficiency specificity delivering mRNA siRNA lung, liver, spleen, respectively. structure-activity relationship (SAR) proves regulation LP structures can provide for systems, demonstrating potential this developing selective open up more possibilities therapy.