Self‐Amplifying RNA‐Based Therapeutics: Advances, Challenges, and Future Perspectives

mRNA therapeutics have garnered significant attention in recent years due to their remarkable success in addressing unmet medical needs across diverse fields, including infectious diseases, cancer, and hereditary disorders. Among the various modalities of mRNA therapeutics, self-amplifying mRNA (saRNA) has emerged as a particularly promising platform. Distinguished by its ability to achieve robust protein expression at lower doses, saRNA offers several advantages, including higher cumulative expression levels and significantly extended expression durations. But the questions of how and where saRNA technology will evolve in the coming years remain underexplored. In this review, we provide a comprehensive overview of saRNA therapeutics, beginning with a detailed explanation of their underlying mechanism of action. We then systematically summarize the preclinical and clinical advancements in saRNA-based therapies, highlighting their applications across a broad spectrum of diseases. We then discuss the key challenges currently faced by saRNA therapeutics and propose potential strategies to overcome these barriers. Finally, we outline future directions for the field, emphasizing the transformative potential of saRNA in clinical applications. In summary, the unique properties of saRNA have positioned it as an innovative tool for the treatment of various diseases, unlocking more possibilities for clinical applications.