Loughrey David, Dahlman James E
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Georgia 30332, United States.
Acc Chem Res. 2022 Jan 4;55(1):13-23. doi: 10.1021/acs.accounts.1c00601. Epub 2021 Dec 3.
mRNA drugs can preempt infectious disease and treat Mendelian disorders, such as sickle cell anemia, muscular dystrophy, and cystic fibrosis, as well as autoimmunity and cancer. The three major therapeutic areas for which mRNA delivery is currently being explored are antigen production, including the COVID-19 vaccine, protein replacement therapy, and genome engineering. It was demonstrated 30 years ago that introducing transcribed mRNA intramuscularly results in detectable protein expression for specific antigens protecting against the likes of influenza and cancer. Utilizing mRNA as a therapeutic modality, however, is challenging. mRNA is large and anionic and, as a result, cannot passively diffuse across the negatively charged plasma membrane. In addition, RNases present in the bloodstream and tissues rapidly degrade mRNA, and its administration induces the innate immune response. In consequence, lipid-, polymer-, dendrimer-, and natural membrane-based mRNA drug delivery systems have been developed to deliver mRNA to target cells. Significant efforts and investments have been made to translate some of these systems into the clinic. Specifically, systemically administered lipid nanoparticles (LNPs) have delivered mRNA to the liver, and intramuscularly administered LNPs have delivered mRNA to immune cells to protect against coronavirus disease of 2019. However, clinically relevant delivery in non-liver tissues such as the spleen, lungs, heart, eye, central nervous system, and lymphatics requires improved drug delivery systems.In this Account, we provide an overview of key advances that have led us to Food and Drug Administration approval for the Pfizer/BioNTech mRNA-based vaccine against SARS-CoV-2 and Emergency Use Authorization for the Moderna mRNA-based vaccine against the same disease, and we explain how these developments will contribute to the clinical translation of mRNA therapeutics targeted outside of the liver. We first focus on the chemical modifications and sequence optimization that can improve the potency of mRNA, resulting in greatly improved pharmacokinetics. After detailing what makes an ideal mRNA payload, we review drug delivery systems used to deliver the payload into target cells. We describe efforts to reduce clearance by the liver, a key obstacle to the development of non-liver therapies. We then consider recent examples of nanoparticles that have delivered mRNA to non-liver tissues. Finally, we discuss current clinical mRNA programs, focusing on the COVID vaccines and highlighting lessons that may be applied to future mRNA drugs.
信使核糖核酸（mRNA）药物可预防传染病，并治疗孟德尔疾病，如镰状细胞贫血、肌肉萎缩症和囊性纤维化，以及自身免疫性疾病和癌症。目前正在探索mRNA递送的三个主要治疗领域是抗原生产（包括新冠疫苗）、蛋白质替代疗法和基因组工程。30年前就已证明，肌内注射转录的mRNA会导致针对流感和癌症等特定抗原的可检测蛋白质表达。然而，将mRNA用作治疗手段具有挑战性。mRNA体积大且带负电，因此无法被动扩散穿过带负电的质膜。此外，血液和组织中存在的核糖核酸酶（RNase）会迅速降解mRNA，并且其给药会引发先天免疫反应。因此，已经开发出基于脂质、聚合物、树枝状大分子和天然膜的mRNA药物递送系统，以将mRNA递送至靶细胞。人们已经付出了巨大努力并投入资金，将其中一些系统转化为临床应用。具体而言，全身给药的脂质纳米颗粒（LNP）已将mRNA递送至肝脏，而肌内给药的LNP已将mRNA递送至免疫细胞以预防2019冠状病毒病。然而，在脾脏、肺、心脏、眼睛、中枢神经系统和淋巴管等非肝脏组织中实现临床相关递送需要改进的药物递送系统。在本综述中，我们概述了一些关键进展，这些进展使我们获得了美国食品药品监督管理局（FDA）对辉瑞/ BioNTech基于mRNA的抗SARS-CoV-2疫苗的批准，以及对Moderna基于mRNA的同一种疾病疫苗的紧急使用授权，并且我们解释了这些进展将如何促进针对肝脏以外靶点的mRNA疗法的临床转化。我们首先关注可提高mRNA效力从而极大改善药代动力学的化学修饰和序列优化。在详细介绍理想的mRNA有效载荷的特点后，我们回顾用于将有效载荷递送至靶细胞的药物递送系统。我们描述了为减少肝脏清除（非肝脏疗法开发的关键障碍）所做的努力。然后，我们考虑最近将mRNA递送至非肝脏组织的纳米颗粒实例。最后，我们讨论当前的临床mRNA项目，重点是新冠疫苗，并强调可能适用于未来mRNA药物的经验教训。
