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

Abstract Lipid nanoparticles (LNPs) with highly efficient and specific extrahepatic targeting abilities are promising in gene delivery, and the lipopeptides (LPs) with excellent designability and functionality are expected to empower the construction of functional LNPs. 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‐based organ‐specific targeting (POST) LNP screening strategy is constructed, in which lysine‐histidine‐based lipopeptides (KH‐LPs) are designed as highly efficient ionizable components. The optimal KH‐LP LNP screened in vitro shows excellent siRNA/mRNA transfecting ability in various hard‐to‐transfect 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‐activity 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.