Ionizable lipid-assisted efficient hepatic delivery of gene editing elements for oncotherapy  

作　　者：Chunhui Li Tongren Yang Yuhua Weng Mengjie Zhang Deyao Zhao Shuai Guo Bo Hu Wanxuan Shao Xiaoxia Wang Abid Hussain Xing-Jie Liang Yuanyu Huang 

机构地区：[1]School of Life Science,Advanced Research Institute of Multidisciplinary Science,Institute of Engineering Medicine,Key Laboratory of Molecular Medicine and Biotherapy,Beijing Institute of Technology,Beijing,100081,China [2]Department of Radiation Oncology,The First Affiliated Hospital of Zhengzhou University,Erqi,Zhengzhou,450000,China [3]Institute of Molecular Medicine,College of Future Technology,Peking University,Beijing,100871,China [4]Chinese Academy of Sciences(CAS)Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety,CAS Center for Excellence in Nanoscience,National Center for Nanoscience and Technology of China,Beijing,100190,China [5]School of Materials and the Environment,Beijing Institute of Technology,Zhuhai,519085,China

出　　处：《Bioactive Materials》2022年第3期590-601,共12页生物活性材料（英文）

基　　金：This work was supported by the Hu-Xiang Young Talent Program(2018RS3094);the Hunan Provincial Natural Science Foundation of China(2019JJ50196,2018JJ1019);the Natural Science Foundation of Guangdong Province(2019A1515010776);the National Natural Science Foundation of China(31901053,32001008,31871003);the Beijing Nova Program from Beijing Municipal Science&Technology Commission(Z201100006820005);the Beijing-Tianjin-Hebei Basic Research Cooperation Project(19JCZDJC64100);the National Key R&D Program of China(2019YFE0133300);the Young Elite Scientist Sponsorship Program of Beijing Association for Science and Technology(2020-2022),and the Postdoctoral Science Foundation of China(2020M670169);We thank Biological&Medical Engineering Core Facilities(Beijing Institute of Technology)for providing advanced equipment.

摘　　要：CRISPR/Cas9-based gene editing has emerged as a powerful biotechnological tool,that relies on Cas9 protein and single guided RNA(sgRNA)to edit target DNA.However,the lack of safe and efficient delivery carrier is one of the crucial factors restricting its clinical transformation.Here,we report an ionizable lipid nanoparticle(iLP181,pKa=6.43)based on iLY1809 lipid enabling robust gene editing in vitro and in vivo.The iLP181 effectively encapsulate psgPLK1,the best-performing plasmid expressing for both Cas9 protein and sgRNA targeting Polo-like kinase 1(PLK1).The iLP181/psgPLK1 nanoformulation showed uniformity in size,regular nanostructure and nearly neutral zeta potential at pH 7.4.The nanoformulation effectively triggered editing of PLK1 gene with more than 30%efficiency in HepG2-Luc cells.iLP181/psgPLK1 significantly accumulated in the tumor for more than 5 days after a single intravenous injection.In addition,it also achieved excellent tumor growth suppression compared to other nucleic acid modalities such as siRNA,without inducing adverse effects to the main organs including the liver and kidneys.This study not only provides a clinically-applicable lipid nanocarrier for delivering CRISPR/Cas system(even other bioactive molecules),but also constitutes a potential cancer treatment regimen base on DNA editing of oncogenes.

关 键 词：CRISPR/Cas Gene editing Lipid nanoparticle PLK1 Cancer therapy 

分 类 号：R73[医药卫生—肿瘤]