The current trajectory of mRNA research extends beyond the development of translational vaccines or therapeutics to achieving exceptional stability in mRNA structures. Despite significant advancements such as codon optimization, sequence manipulation, and chemical modifications, recognized by the Nobel Prize in Physiology or Medicine in 2023, there remains room for further improvement.
Deadenylation plays a pivotal role in mRNA degradation. The shortening of the poly(A) tail, known as deadenylation, stands as the rate-limiting step in most eukaryotic mRNA degradation processes. Following the truncation of the poly(A) tail, enzymatic degradation occurs either from the 5' to 3' end or vice versa. Remarkably, maintaining the integrity of the poly(A) tail also affects translation. In capdependent translation, for instance, the cap structure forms a complex with initiation factors eIF4E and eIF4G in eukaryotes. Poly(A) tail-binding proteins further stabilize the translation initiation complex by interacting with eIF4G. Therefore, it is reasonable to argue that the poly(A) tail not only enhances mRNA stability but also plays a prominent role in translation.
In a recent publication in Nature Biotechnology, researchers demonstrated a promising method for attaching a branched poly(A) tail to mRNAs. Such a modification has been shown to improve stability. Comparative analysis with canonical mRNA and circRNA revealed that multi-tail mRNA exhibits superior translational efficiency. Furthermore, chemical manipulation residues, relying on Click Chemistry—a class of reactions honored with the Nobel Prize in Chemistry in 2022—did not elicit a long-term immunogenic response. These attributes position multi-tail mRNA as a promising candidate for therapeutic applications.
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