Nucleoside-modified circRNA: Reduced immunogenicity and expansive applications beyond vaccines

mRNA drives the production of functional proteins to achieve therapeutic intervention, rendering it an attractive molecular platform for biomedical applications. In the 1990s, researchers established in vitro transcription (IVT) systems to produce linear mRNA encoding target proteins. Nevertheless, unmodified mRNA exhibits potent immunogenicity and elicits robust innate immune responses in vivo, which brought early translational research of mRNA to a prolonged standstill. In 2005, the Karikó and Weissman team demonstrated that replacing native uridine (U) with chemically modified pseudouridine (ψ) during IVT could drastically reduce mRNA immunogenicity and evade innate immune sensing.