摘要
近年来,信使核糖核酸(messenger RNA,mRNA)疗法作为一种革命性的治疗手段,在遗传性疾病、传染病以及癌症治疗领域展现出巨大潜力.然而,mRNA分子的不稳定性和体内递送的低效性仍是限制其广泛应用的关键挑战.本综述聚焦于脂质纳米颗粒(lipid nanoparticles,LNPs)作为高效载体在mRNA递送系统中的最新进展与应用,系统地概述了mRNA治疗在疫苗、蛋白质替代疗法和基因编辑治疗中的应用,并基于LNP基础四组分的改造、第五组分的引入、表面改性以及机器学习辅助LNP迭代开发等四个方面,详细介绍了工程化修饰LNP的方式以及在治疗中的应用.
Abstract
In recent years,nucleic acid therapy,as a revolutionary therapeutic tool,has shown great potential in the treatment of genetic diseases,infectious diseases and cancer.Lipid nanoparticles(LNPs)are currently the most advanced mRNA delivery carriers,and their emergence is an important reason for the rapid approval and use of COVID-19 mRNA vaccines and the development of mRNA therapy.Currently,mRNA therapeutics using LNP as a carrier have been widely used in protein replacement therapy,vaccines and gene editing.Conventional LNP is composed of four components:ionizable lipids,phospholipids,cholesterol,and polyethylene glycol(PEG)lipids,which can effectively load mRNA to improve the stability of mRNA and promote the delivery of mRNA to the cytoplasm.However,in the face of the complexity and diversity of clinical diseases,the structure,properties and functions of existing LNPs are too homogeneous,and the lack of targeted delivery capability may result in the risk of off-targeting.LNPs are flexibly designed and structurally stable vectors,and the adjustment of the types or proportions of their components can give them additional functions without affecting the ability of LNPs to deliver mRNAs.For example,by replacing and optimizing the basic components of LNP,introducing a fifth component,and modifying its surface,LNP can be made to have more precise targeting ability to reduce the side effects caused by treatment,or be given additional functions to synergistically enhance the efficacy of mRNA therapy to respond to the clinical demand for nucleic acid therapy.It is also possible to further improve the efficiency of LNP delivery of mRNA through machine learning-assisted LNP iteration.This review can provide a reference method for the rational design of engineered lipid nanoparticles delivering mRNA to treat diseases.
维普
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