Core Viewpoint - The development of mRNA and lipid nanoparticles (LNP) has shown significant clinical success in delivering gene drugs to the liver, but the tendency of LNP to accumulate in the liver poses a major bottleneck for broader applications in gene therapy [2][4]. Group 1: Research Development - A collaborative research paper titled "Tissue-specific mRNA delivery and prime editing with peptide–ionizable lipid nanoparticles" was published in Nature Materials, showcasing a new platform for organ-targeted mRNA delivery [3]. - The research combines peptides and ionizable lipids to create a novel material called peptide-ionizable lipid (PIL), establishing a platform (PILOT) for organ-specific and tunable mRNA delivery [4][5]. Group 2: Engineering and Design - Researchers have invested significant effort into engineering mRNA-LNP to reach organs beyond the liver, utilizing ligand coupling, component optimization, and the development of new ionizable lipids [7]. - The study highlights the importance of ionizable lipids in determining the efficacy and organ selectivity of LNP, with a focus on customizing lipid structures through combinatorial chemistry [7][8]. Group 3: Synthesis and Modifications - The research team developed over 120 structurally diverse PILs using solid-phase supported synthesis (SPSS), which offers advantages over traditional liquid-phase synthesis [9]. - Specific modifications to amino acids, such as lysine and arginine, enhance mRNA delivery to the lungs, while cysteine and histidine modifications target the liver [11]. Group 4: Efficacy and Safety - The PILOT platform demonstrated effective delivery of Cre mRNA, achieving specific gene editing in targeted tissues, with editing efficiencies of 13.1% in the liver and 7.4% in the lungs [13]. - The study provides a universal design strategy for developing organ-targeted ionizable lipids, indicating the potential of the PILOT LNP platform in advancing organ-specific gene editing therapies [15].