SORT团队出手：“三脚架”结构，让LNP高效、选择性靶向肺部

Core Viewpoint - The recent advancements in mRNA vaccines and genome editing therapies rely on the development and engineering of lipid nanoparticles (LNPs), which are non-viral delivery systems that effectively protect nucleic acids and deliver them to cells [3][4]. Group 1: Development of Targeted Delivery Systems - The research team led by Professor Daniel Siegwart developed organ-specific targeting LNPs, known as SORT-LNP, which enable mRNA delivery to organs outside the liver, such as the lungs and kidneys [3]. - A new study published in Nature Biomedical Engineering introduced tripod-like lung-targeting (LuT) lipids for constructing novel LNPs, achieving highly efficient and selective gene delivery and editing to the lungs [4]. Group 2: Design and Evaluation of LuT Lipids - The study systematically described the design, chemical synthesis, and biomedical evaluation of two lipid libraries, resulting in the synthesis of 444 quaternary ammonium lipids [7]. - The optimal LuT lipid features a unique "tripod-like" structure, consisting of a quaternary ammonium head as the core, three long alkyl chains as "legs," and a short chain as a "handle" [7]. - The screening process yielded a high success rate, with 39% of candidates from the first library and 67% from the second library demonstrating excellent performance [7]. Group 3: Performance and Implications of LuT LNPs - The best-performing LuT LNP, named 1A7B13 LNP, showed a 25.5-fold increase in mRNA delivery efficiency compared to the benchmark DOTAP SORT LNP and a 9.2-fold increase in gene editing efficiency using CRISPR–Cas9, with over 90% selectivity for lung delivery [9]. - The delivery of IL-10 mRNA via 1A7B13 LNP demonstrated promising therapeutic effects for acute lung injury, highlighting the relationship between lipid structure and lung-targeting activity [9].