Silencing the alarm: nucleoside modifications suppress innate immune sensing of RNA

This Pillars of Immunology article is a commentary on “Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA,” a pivotal article by K. Karikó, M. Buckstein, H. Ni, and D. Weissman, and published in Immunity in 2005.1 https://www.cell.com/immunity/fulltext/S1074-7613(05)00211-6. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA-based vaccines saved millions of lives during the coronavirus disease 2019 (COVID-19) pandemic, clearly validating the viability of this groundbreaking platform technology.2 Although the development of COVID-19 mRNA vaccines took less than a year in 2020, decades of research went into the creation of the vaccine modality itself. Indeed, the first report investigating mRNA as a therapeutic strategy was published in 1990, when researchers demonstrated that in vitro–transcribed, synthetic mRNA directly injected into mouse skeletal muscle produced protein in vivo.3 A subsequent study, in 1992, illustrated that injecting mRNA encoding vasopressin into the hypothalamus triggered a physiological response in rats.4 Despite these promising early data, mRNA research remained largely unexplored due to concerns surrounding RNA instability, high inflammatory potential, and inefficient in vivo delivery methods and materials. Of these hurdles, RNA’s capacity to strongly activate the innate immune system presented an enormous challenge and posed a serious safety concern for its use as human medicine. Research in the 2000s by Karikó and Weissman exploring RNA biochemistry and, specifically, the use of modified nucleosides in synthetic mRNA established our understanding and the feasibility of mRNA for vaccines and many other applications today. The seminal 2005 paper in Immunity by Karikó et al. evaluated how RNA nucleoside modification decreased its sensing by innate immune receptors, paving the way for a wide range of potential future biomedical applications.1 Karikó and Weissman were awarded the Nobel Prize in Physiology or Medicine in 2023 for their discoveries in the 2000s, which were crucial to the development of COVID-19 mRNA vaccines.