Strategies to Improve the Stability and Translation of Therapeutic mRNAs

Therapeutic messenger RNAs (mRNAs) offer a versatile platform for treating a wide range of diseases, but their clinical efficacy hinges on optimizing both stability and translational efficiency. This review summarizes recent advances in strategies to enhance mRNA performance, with a focus on human therapeutics. We discuss secondary structure optimization, including artificial intelligence-guided design tools like RNAdegformer and LinearDesign, which balance structural stability and translational output. The roles of 5' and 3' untranslated regions in ribosome recruitment and mRNA decay are examined, highlighting sequence motifs and empirical design strategies that facilitate these processes. Chemical modifications, such as pseudouridine substitution, are shown to improve stability and reduce immunogenicity. Emerging approaches using circular RNA further extend transcript longevity. Finally, we review delivery technologies, including lipid nanoparticles, polymers, and extracellular vesicles, that protect mRNA and enable targeted cellular uptake. Together, these advances provide a road map for developing stable, efficient, and clinically viable mRNA-based therapeutics.