开启mRNA技术实用化大门的钥匙——浅析2023年度诺贝尔生理学或医学奖

The key to practical application of mRNA technology:A brief analysis of the 2023 Nobel Prize in Physiology or Medicine

在现代生命的中心法则中,RNA是遗传信息的传递者和重要的调控者.其中,信使RNA(messenger RNA,mRNA)作为中间分子,将DNA编码的信息传递到蛋白质序列,因而在发挥疫苗和药物功能时具备许多独特的优势.从1961年mRNA的发现到2020年新型冠状病毒感染全球大流行期间的mRNA疫苗接种,mRNA技术经历近60年的发展,最终进入了大规模的临床应用阶段.在这一过程的早期,科学家们陆续突破了mRNA的实验室合成、在细胞内表达蛋白质、递送进入动物体内等多种技术,但mRNA自身具有的免疫原性限制了其在人体内的进一步应用,成为了制约mRNA技术实用化的关键技术瓶颈.2023年度诺贝尔生理学或医学奖授予了Katalin Karikó和Drew Weissman,以表彰他们在核苷碱基修饰方面的发现.这一发现使mRNA技术突破了进入人体之后的安全性瓶颈,使得在新型冠状病毒感染大流行期间快速开发出有效mRNA疫苗成为可能.本文将对2023年度诺贝尔生理学或医学奖进行解读,并通过mRNA技术的“前世今生”浅析这一技术的重要意义.

The 2023 Nobel Prize in Physiology or Medicine was awarded to Katalin Karikóand Drew Weissman in recognition of their contributions to mRNA technology.Before this groundbreaking discovery,mRNA was known to be unstable and can induce inflammatory reactions.Without overcoming this challenge,the progression of mRNA technology towards clinical applications would be hindered.In 2005,Katalin Karikóand Drew Weissman discovered that,unlike naturally synthesized mRNA,in vitro transcribed mRNA led to adverse inflammatory reactions through the release of pro-inflammatory cytokines after being recognized by dendritic cells(DC)as a foreign molecule and subsequent activation of toll-like receptor 3(TLR3).With this knowledge,they further discovered that,by introducing naturally occurring modified nucleotides to substitute unmodified nucleotides during in vitro transcription,the activation of monocyte-derived dendritic cells(MDDC)induced by mRNA containing these modified nucleotides was significantly reduced and the inflammatory reactions could be nearly eliminated.This discovery has overcome the safety bottleneck of mRNA,unleashing the potential of mRNA technology.In the following years,with more technological breakthroughs in lipid nanoparticle(LNP)-based delivery method and large-scale mRNA production,the advantages of mRNA technology in terms of standardized development,safety,and effectiveness have become evident,and has begun to facilitate new technological breakthroughs in the prevention of infectious diseases and the treatment of cancer,genetic disorders,and autoimmune diseases.For infectious diseases that lack effective vaccines,the advantages of mRNA vaccines have ushered in new approaches to solving challenges such as encoding multiple proteins in a single vaccine and targeting rapidly evolving viruses.In addition to preventing infectious diseases,the characteristic of mRNA to express any protein within the body brought it a flexible“body reprogramming”capability,allowing the intervention for various internal abnormalities caused by multiple factors such as genetic disease,cancer,autoimmune diseases,and aging.Promising mRNA-based therapeutics have been developed targeting various inherited metabolic diseases as well as malignant tumors,and mRNA-based chimeric antigen receptor(CAR)T-cell therapy has displayed dramatically reduced complexity and cost.As if a key that opened a giant gateway,the technological breakthrough of Katalin Karikóand Drew Weissman has made the practical application of various mRNA technologies possible and allowed mRNA technologies to enter a new stage of development,which eventually played a crucial role in the global response to the coronavirus disease 2019(COVID-19)pandemic.It has brought a paradigm shift in how we approach infectious diseases and shed new light on the treatment of incurable diseases.Therefore,this achievement has earned the prestigious 2023 Nobel Prize in Physiology or Medicine.This paper reviews the early research trajectory of mRNA technology and the technical challenges encountered during its transition into practical applications,interprets Katalin Karikóand Drew Weissman’s technological breakthroughs,and provides a brief analysis of the new opportunities that mRNA technology presents to the field of medicine.By exploring the“past and present”of mRNA technology,this paper aims to highlight the profound significance and transformative impact of the achievement that was awarded the 2023 Nobel Prize in Physiology or Medicine.