mRNA-based therapies: From molecular discovery to clinical revolution

For nearly 50 years, scientists have sought to exploit messenger RNA (mRNA) as a therapeutic tool, overcoming major challenges related to instability, delivery, and inflammatory reactions. A major breakthrough came with the incorporation of modified nucleosides, particularly pseudouridine, during in vitro mRNA synthesis, which markedly improved stability, translation efficiency, and tolerability. The clinical success of mRNA technology was demonstrated in 2020 with the development of highly effective and safe COVID-19 vaccines, administered to over a billion individuals worldwide. These achievements inaugurated a new era in molecular medicine. In this review, we revisit the historical development of mRNA delivery into human cells and discuss the emergence of mRNA as a gene-therapy approach. In fact, beyond vaccination, mRNA platforms are rapidly expanding toward protein replacement therapies for genetic disorders and innovative strategies for cancer treatment. We summarize advances in synthetic mRNA design and optimization, delivery vehicles, and administration strategies that enable therapeutic applications. Finally, we highlight current limitations, technological challenges, and future opportunities, emphasizing how mRNA-based technologies have become powerful tools for studying gene function and developing next-generation precision therapies.