mRNA technology has become an integral part of our lives due to the pandemic caused by the SARS-CoV-2 virus. More than 60 years of investment in the technology led to the development of various vaccine designs in a very short timeframe. However, our current understanding should not limit its applications. mRNA technology has the potential to be employed not only for the development of vaccines but also for therapeutics, including personalized cancer treatment.
In the classical design of mRNA, the 5'-end has a cap that is essential for high translational efficiency, as uncapped mRNA is barely translated and highly immunogenic. The 5'-cap is crucial for recognition by the translation initiation factor eIF4E. However, the current state of the art lacks direct control over when and where mRNAs are translated. To address this, scientists from Westfälische Wilhelms-Universität Münster developed a light-controlled mRNA design.
As it was employed in immolative polymer designs, the photo cleavable group was connected to the N²-position of guanosine moiety in Cap 0 structure via self-immolative carbamate linkage, leading to FlashCaps. FlashCaps are compatible with the current mRNA synthesis techniques. mRNAs with FlashCaps are translationally muted unless they are activated by light. Upon light activation, the release of Cap 0 structure was demonstrated in different cell lines. In HeLa cells, an up to 32-fold increase in translation was achieved via light-activation. The chemical modification of 5'-cap also prevents the recognition of mRNAs from decapping enzyme Dcp1/2, leading to an overall higher stability against exonucleases. Thus, such a cap design is an immense tool to activate mRNAs whenever and wherever as long as light can be transferred efficiently.
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