The Evolving Landscape of mRNA Therapeutics: From Molecular Design and Advanced Delivery Systems to Clinical Translation and Future Vistas

The messenger RNA (mRNA) therapeutic platform has transitioned from a theoretical concept to a clinically validated, transformative modality in contemporary medicine. The unprecedented success of the COVID-19 vaccines, which accelerated global recognition of this technology, has catalyzed an intensive and broad exploration across numerous therapeutic domains. This review provides an integrated examination of the molecular and engineering innovations that have underpinned the platform's maturation. Collective advances, including refinements in cap analog chemistry, the meticulous optimization of untranslated regions and the poly(A) tail, precise tuning of codon usage, and strategic nucleoside modification, have synergistically enhanced mRNA stability, translational efficiency, and immune tolerance. Concurrently, the parallel evolution of lipid nanoparticles (LNPs) design, specifically the development of ionizable and biodegradable lipids, has established a reproducible and safe framework for highly efficient in vivo delivery. Furthermore, the review considers next-generation constructs, such as circular RNA (circRNA) and self-amplifying RNA (saRNA), which hold the distinct promise of extending expression durability and substantially reducing required dosing regimens. Emerging applications now extend beyond vaccination to oncology, rare genetic and metabolic diseases, and immune modulation. Despite these advances, major challenges persist in achieving extrahepatic delivery, improving endosomal escape, and enabling thermostable, scalable manufacturing. Continued integration of molecular engineering, data-driven design, and nanotechnology is expected to transform mRNA into a modular, programmable therapeutic platform. Collectively, these developments position mRNA therapeutics at the forefront of precision and regenerative medicine, defining a new trajectory for next-generation biologics.