mRNA Stability: An Unresolved Challenge for Broad Therapeutic Applications

From infectious diseases and cancers to various rare diseases, mRNAs have demonstrated considerable therapeutic potential for a wide range of diseases. However, due to their single-stranded structure, mRNA molecules are vulnerable to enzyme-mediated degradation. Therefore, the inherent instability of mRNA poses a significant challenge. In this review, we explore strategies to slow down the degradation rate, such as removing degradative enzymes, adding protective substances, and optimizing storage and transport conditions to enhance mRNA stability. Furthermore, optimizing the sequence and structure of mRNAs is crucial for improving stability, which can be significantly aided by fine-tuning the sequences of the 5' untranslated region, open reading frame, and 3' untranslated region, along with introducing various RNA modifications. The design of novel mRNA structures, including circular mRNA and self-amplifying RNA, also offers novel approaches for enhancing mRNA stability. Additionally, we briefly introduce the use of mRNA delivery materials for improving stability and discuss current challenges and future directions in mRNA development. With ongoing technological advancements and the gradual maturation of the market, mRNA is set to play an increasingly significant role in versatile biotechnology fields.