可电离脂质及其对载核酸药物脂质纳米粒转染效率和安全性的影响研究进展  

Research progress in ionizable lipids and their effects on transfection efficiency and safety of nucleic acid-carrying drug lipid nanoparticles

作　　者：何凤阳 刘媛媛 孟庆斌 刘许歌 张菡 HE Fengyang;LIU Yuanyuan;MENG Qingbin;LIU Xuge;ZHANG Han(School of Pharmacy,Henan University,Kaifeng 475004,China;Academy of Military Medical Sciences,Beijing 100850,China)

机构地区：[1]河南大学药学院,河南开封475004 [2]军事医学研究院,北京100850

出　　处：《中国药理学与毒理学杂志》2024年第6期462-472,共11页Chinese Journal of Pharmacology and Toxicology

基　　金：国家自然科学基金(22171286)。

摘　　要：可电离脂质构成的脂质纳米粒(LNP)是目前临床上最具应用前景的非病毒核酸药物递送载体之一,在递送基因治疗药物和疫苗等方面具有巨大潜力。LNP的主要成分可电离脂质对LNP的内涵体逃逸率、转染效率、器官靶向性和安全性等起决定性作用。可电离脂质的亲水头基含有叔胺基,可提高LNP缓冲能力,进而改变其p Ka值,并含有咪唑,可增强mRNA-LNP的稳定性和转染活性;连接体含有酯基能够高效诱导基因沉默并可提高其降解速率和安全性;疏水尾数量在3~4个,具有1~2个不饱和度和8~18个碳链长度时,LNP能够高效诱导基因沉默,同时含有分支或不对称的疏水尾时可提高LNP的转染效率。本综述从可电离脂质的化学结构出发,总结了其结构对载核酸药物LNP的转染效率和安全性的影响,并总结归纳其构效关系,为新型可电离脂质的研究提供借鉴。Lipid nanoparticles(LNPs),composed of ionizable lipids,are currently the most promis⁃ing non-viral nucleic acid drug delivery vectors in clinical practice,and have great potential in gene ther⁃apy drug delivery and vaccine delivery.Ionizable lipids,the main components of LNPs,play a decisive role in the endosome escape rate,transfection efficiency,organ targeting and safety of LNPs.Among them,the hydrophilic head group of ionizable lipids contains tertiary amine groups,which can improve the buffering capacity of LNPs and thus change the pKa value,and imidazole can enhance the stability and transfection activity of mRNA-LNP.The ligand contains ester groups,which can induce gene silencing efficiently and improve the degradation rate and safety.When the number of hydrophobic tails is 3-4,with 1-2 unsaturation and 8-18 carbon chain length,LNPs can effectively induce gene silencing.Meanwhile,the presence of branching or asymmetric hydrophobic tails can improve the transfection efficiency of LNPs.Based on the chemical structure of ionizable lipids,this review summarizes the influ⁃ence of the structure of ionizable lipids on the transfection efficiency and safety of nucleic acid carrying drugs LNPs,and the structure-activity relationship of ionizable lipids so as to provide reference for studies on novel ionizable lipids.

关 键 词：可电离脂质 脂质纳米粒 构效关系 核酸药物 

分 类 号：R96[医药卫生—药理学] R914[医药卫生—药学]