“More” Artificial mRNAs: Beyond the Art of Nature

Messenger RNA (mRNA) has emerged as a versatile platform for gene expression and therapeutic innovation. Early engineering efforts focused on optimizing canonical mRNA components-the 5' cap, untranslated regions, coding sequence, and poly(A) tail-to enhance stability, translational efficiency, and safety. These refinements culminated in the success of mRNA vaccines and consequently enabled diverse biomedical applications ranging from gene and cell therapy to genome editing. More recently, research has expanded beyond the structural constraints of natural mRNAs, giving rise to non-canonical architectures, such as circular, branched, self-amplifying, and lantern-shaped RNAs. These designs confer novel properties, including resistance to degradation, autonomous replication, and programmable control of translation. Progress in chemical modification, ribozyme engineering, and RNA nanotechnology has further accelerated the diversification of synthetic mRNA. Together with advances in synthesis, purification, and delivery technologies, these innovations are transforming mRNA from a transient messenger into a designable molecular system. This review revisits the evolution of mRNA engineering-from natural optimization to creative structural redesign-and outlines emerging concepts that illustrate how synthetic mRNA is expanding the possibilities of gene expression control.