Beyond the Sequence: Chemical and Topological Design and Innovations in mRNA Therapeutics

Messenger RNA (mRNA) has rapidly emerged as a transformative therapeutic modality, exemplified by its growing applications in infectious diseases, oncology, and genetic disorders. The chemical programmability of mRNA allows researchers to modulate its function by introducing synthetic modifications across the molecule─from the cap structure, untranslated regions (UTRs), coding sequence (CDS) to poly(A) tail and from base, backbone to ribose sugars. Beyond sequence-level design, recent advances have introduced a new dimension of control: topological engineering. Circular RNAs, branched structures, and synthetic lariat architectures are reshaping how we approach RNA stability, immunogenicity, and translation. This review surveys recent advances in the chemical and topological engineering of mRNA, emphasizing four key areas: (1) enzymatic, chemical, and hybrid methodologies that expand the repertoire of accessible mRNA modifications; (2) synthesis strategies for linear, circular, and branched mRNA topologies; (3) structure-activity relationships governing translation efficiency, decay, and immune activation; and (4) implications for next-generation mRNA-based therapeutics. By integrating chemical synthesis, synthetic biology, and RNA structural design, researchers are beginning to unlock the full therapeutic potential of engineered mRNA molecules.