【摘要】 信使核糖核酸(mRNA)是由DNA的一条链作为模板转录而来的携带遗传信息、指导蛋白质合成的一类单链核糖核酸.随着mRNA体外合成中修饰调控/序列优化系统的日益完善和体内递送系统的逐渐成熟, mRNA缺乏稳定性及无法有效递送等缺点已经逐渐被克服,基于mRNA的治疗方法已逐步成为研究热点.通过体外转录技术合成的mRNA,借助脂质纳米颗粒递送系统运送到特定的组织细胞内,由细胞自身的翻译系统翻译出目标蛋白.这些蛋白或是作为抗原激发免疫反应,或是补充细胞内缺少的蛋白以行使功能,最终达到治疗的目的. mRNA治疗具有的制备快速、成本低、安全等优点让它在众多治疗方法中脱颖而出,被广泛地应用于癌症疫苗、感染性疾病疫苗、蛋白替代治疗和罕见病治疗等领域.为了解全球mRNA治疗的开发和研究现状,本文重点对mRNA治疗的修饰调控/序列优化系统、递送系统以及临床研究现状进行分析和总结.更多还原

【Abstract】 The striking effectiveness of messenger ribonucleic acid(mRNA) vaccines against coronavirus disease 2019(COVID-19)not only offers hope to end the current pandemic, but also presents mRNA-based therapeutics as a potential new treatment class that may help in the fight against other diseases. In vitro-transcribed(IVT) mRNA is engineered to structurally resemble naturally occurring mature and processed eukaryotic mRNA. Such synthetic mRNAs deliver genetic information that allows the translational machinery of the host cells to produce many copies of the encoded proteins, which can function as antigens to boost immune responses or as supplementary beneficial proteins, resulting in a therapeutic effect. With recent developments in mRNA in vivo delivery platforms and the improvement of modified regulatory systems, the stability and transfection efficiency of mRNA have been greatly improved. Modified regulatory systems utilize caps, 5′ and 3′untranslated regions, open reading frames, Poly(A) tails, and chemically modified nucleotides. Notably, in vivo delivery platforms can either be a non-targeted or targeted delivery system.Currently, mRNA-based therapeutics, including vaccines and protein replacement therapy, are being clinically developed for cancers, infectious diseases, and rare diseases. Common mRNA cancer vaccines include dendritic cell mRNA cancer vaccine, naked mRNA injection, mRNA encoding CAR, and other combination therapies. There are two main types of mRNA vaccines against infectious diseases: Non-replicating and self-amplifying. In addition, mRNA protein replacement therapies are available; these are therapies in which body cells are transfected with mRNA, and the translated proteins are used to supplement the lack of proteins in the body or replace abnormal proteins that hinder normal cellular pathways.mRNA therapies are also used in treatment of rare genetic diseases, such as Fabry disease, methylmalonic acidemia,ornithine carbamoyltransferase deficiency, and acute intermittent porphyria. Furthermore, IVT mRNA encoding genomeediting nucleases has been used as a novel method to perform gene editing.mRNA therapies have the advantages of fast preparation, low production costs, and safety. However, there are still challenges to be overcome for the successful clinical application of mRNA-based therapies. For example, mRNA stability and target specificity still require improvement. In terms of stability, quality control needs to be improved and the negative impact of immunogenicity should be reduced. Quality control refers to improving the ability to detect residual template deoxyribonucleic acid, IVT reaction by-products, and incomplete mRNA. In addition, when comparing independent routes of administration, the variation between-and within individuals, particularly due to the mRNA dosage and protein effects has not been thoroughly studied.To understand the up-to-date development and research status of mRNA therapies, this review focuses on molecular design, delivery system, and clinical research status of mRNA therapies.更多还原