组织特异性mRNA-LNP递送技术的研发策略  

Recent advances in strategies for developing tissue-selective mRNA-LNP technology

作　　者：宗岩 魏妥 程强 Yan Zong;Tuo Wei;Qiang Cheng(Department of Biomedical Engineering,College of Future Technology,Peking University,Beijing 100871,China;State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;Beijing Institute for Stem Cell and Regenerative Medicine,Beijing 100101,China)

机构地区：[1]北京大学未来技术学院,生物医学工程系,北京100871 [2]中国科学院动物研究所,干细胞与生殖生物学国家重点实验室,北京100101 [3]北京干细胞与再生医学研究院,北京100101

出　　处：《科学通报》2024年第33期4795-4804,共10页Chinese Science Bulletin

基　　金：国家自然科学基金(82272139);中央高校基本科研业务费北京大学新工科交叉青年专项(PKU2023XGK011);国家重点研发计划(2022YFA1103802)资助。

摘　　要：新型冠状病毒疫苗的成功研发将信使RNA(messenger RNA, mRNA)技术在全球范围推到了全新高度,更是直接推动了我国mRNA医药产业的快速崛起和发展. mRNA技术成功的背后离不开安全、高效的递送载体,尤其是脂质纳米颗粒(lipid nanoparticle, LNP),已获批(包括正式获批和紧急使用授权)的mRNA新冠疫苗大多受益于此递送体系,临床在研的mRNA药物项目超90%也同样依赖于LNP.作为mRNA递送领域炙手可热的明星载体, LNP自身的研发备受关注.当前mRNA-LNP技术在肝脏递送、肌肉注射的相关生物医学应用中较为成熟,但针对肝外组织的靶向递送相对处在研究早期.为了最大化扩宽mRNA药物的应用场景,研究者已经采取多种技术手段研发LNP靶向递送技术.基于此,本文重点讨论了当前组织靶向mRNA-LNP技术的研究策略,包括LNP处方优化、筛选新型脂质分子、靶向抗体修饰、给药方式优化等,并简要展望本领域未来的可能发展方向.The approval of mRNA vaccines for coronavirus disease 2019(COVID-19)has garnered significant attention for mRNA technology worldwide.This milestone has had a profound impact on the industrial transformation of mRNA in China,as evidenced by the increased number of startups and financing events in the past 2-3 years.Regarding mRNA itself,in addition to implementing chemical modifications,such as pseudouridine and N1–methyl pseudouridine,to avoid innate immune responses,efforts have been made to enhance stability and scale up production to meet clinical needs.Also,the successful application of mRNA technology heavily relies on safe and efficient delivery vehicles,particularly lipid nanoparticles(LNP).The initially approved mRNA COVID-19 vaccines,Comirnaty and Spikevax,have benefited from this delivery system.Furthermore,more than 90%of mRNA drug programs in clinical research,including cancer vaccines,infectious disease vaccines,and therapeutics for inherited genetic disorders,also depend on LNP vectors.Notably,mRNA-4157,an mRNA-LNP cancer vaccine for melanoma developed by Moderna and Merck,demonstrated positive results in clinical trials and was granted Breakthrough Therapy Designation(BTD)by the Food and Drug Administration(FDA).LNP typically consists of four components:ionizable cationic lipid,phospholipid,cholesterol,and PEGylated lipid.Each component plays a crucial role in the stability,function,efficacy,and safety of LNP.The ionizable cationic lipid,in particular,is considered a key component and researchers invest substantial efforts in designing and screening ionizable lipids.These lipids can interact with mRNA molecules(which are negatively charged)through electrostatic interactions,encapsulating them in a low pH buffer.The charge is then neutralized upon buffer exchange to a physiological pH(pH 7.4).Once internalized by cells,the ionizable lipids can regain their positive charge within endosomes/lysosomes to facilitate mRNA release into the cytoplasm for translation.Phospholipid and cholesterol serve as

关 键 词：脂质纳米颗粒 mRNA治疗 组织靶向递送 纳米医学 

分 类 号：R943[医药卫生—药剂学]