MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Zheda Road 38, Hangzhou 310027, China.
Life Sciences Institute, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, China.
Acta Biomater. 2021 Sep 1;131:1-15. doi: 10.1016/j.actbio.2021.06.020. Epub 2021 Jun 13.
Synthetic modified messenger RNA (mRNA) has manifested great potentials for therapeutic applications such as vaccines and gene therapies, with the recent mRNA vaccines for global pandemic COVID-19 (corona virus disease 2019) attracting the tremendous attention. The chemical modifications and delivery vehicles of synthetic mRNAs are the two key factors for their in vivo therapeutic applications. Chemical modifications like nucleoside methylation endow the synthetic mRNAs with high stability and reduced stimulation of innate immunity. The development of scalable production of synthetic mRNA and efficient mRNA formulation and delivery strategies in recent years have remarkably advanced the field. It is worth noticing that we had limited knowledge on the roles of mRNA modifications in the past. However, the last decade has witnessed not only new discoveries of several naturally occurring mRNA modifications but also substantial advances in understanding their roles on regulating gene expression. It is highly necessary to reconsider the therapeutic system made by synthetic modified mRNAs and delivery vectors. In this review, we will mainly discuss the roles of various chemical modifications on synthetic mRNAs, briefly summarize the progresses of mRNA delivery strategies, and highlight some latest mRNA therapeutics applications including infectious disease vaccines, cancer immunotherapy, mRNA-based genetic reprogramming and protein replacement, mRNA-based gene editing. STATEMENT OF SIGNIFICANCE: The development of synthetic mRNA drug holds great promise but lies behind small molecule and protein drugs largely due to the challenging issues regarding its stability, immunogenicity and potency. In the last 15 years, these issues have beensubstantially addressed by synthesizing chemically modified mRNA and developing powerful delivery systems; the mRNA therapeutics has entered an exciting new era begun with the approved mRNA vaccines for the COVID-19 infection disease. Here, we provide recent progresses in understanding the biological roles of various RNA chemical modifications, in developing mRNA delivery systems, and in advancing the emerging mRNA-based therapeutic applications, with the purpose to inspire the community to spawn new ideas for curing diseases.
合成修饰信使 RNA（mRNA）在疫苗和基因治疗等治疗应用中表现出巨大的潜力，最近用于全球大流行 COVID-19（2019 年冠状病毒病）的 mRNA 疫苗引起了极大的关注。合成 mRNA 的化学修饰和递送载体是其体内治疗应用的两个关键因素。核苷甲基化等化学修饰赋予合成 mRNA 高稳定性和降低先天免疫刺激。近年来，合成 mRNA 的规模化生产以及高效 mRNA 配方和递送策略的发展显著推动了该领域的发展。值得注意的是，我们过去对 mRNA 修饰的作用知之甚少。然而，过去十年不仅见证了几种天然存在的 mRNA 修饰的新发现，也在理解它们在调节基因表达中的作用方面取得了实质性进展。有必要重新考虑由合成修饰 mRNA 和递送载体组成的治疗系统。在这篇综述中，我们将主要讨论各种化学修饰对合成 mRNA 的作用，简要总结 mRNA 递送策略的进展，并重点介绍一些最新的 mRNA 治疗应用，包括传染病疫苗、癌症免疫疗法、基于 mRNA 的基因重编程和蛋白质替代、基于 mRNA 的基因编辑。
意义声明：合成 mRNA 药物的发展前景广阔，但由于其稳定性、免疫原性和效力方面的挑战性问题，在很大程度上落后于小分子和蛋白质药物。在过去的 15 年中，通过合成化学修饰的 mRNA 和开发强大的递送系统，这些问题得到了实质性的解决；mRNA 疗法已经进入了一个激动人心的新时代，随着用于 COVID-19 感染疾病的 mRNA 疫苗获得批准。在这里，我们提供了在理解各种 RNA 化学修饰的生物学作用、开发 mRNA 递送系统以及推进新兴的基于 mRNA 的治疗应用方面的最新进展，目的是激发科学界为治疗疾病带来新的思路。
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