Today Yaohai Bio-Pharma summarized the latest research results of two mRNA giants in targeted delivery, focusing on the perspective of mRNA sequence design and optimization, and combining publicly available patents and literature.

The application of mRNA technology is promising and has gradually expanded from infectious disease vaccines to cancer vaccines, protein replacement therapy, tumor immunotherapy, cell reprogramming and gene editing. To achieve the clinical effects of mRNA, it is necessary to ensure that the mRNA molecules reach specific target cells and then efficiently express proteins with biological functions.

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The extension of mRNAs to multiple applications is dependent on advances in targeted delivery, including sequence design, optimization of delivery systems, and local drug delivery. Overall, both Moderna and CureVac draw on microRNA (miRNA) or miRNA-binding sites, with the difference that Moderna did so by initiating translation of the target mRNA in target cells, while CureVac inhibited the expression of the target mRNA at off-target sites outside of the target cell.

Moderna

Moderna's mRNA-targeted delivery strategy is based on miRNAs and inhibitor proteins initiating the expression of target mRNAs in specific cells.

CureVac

CureVac's mRNA-targeted delivery strategy differs from Moderna's strategy of targeting tissues to initiate expression, but instead inhibits mRNA expression in non-targeted tissues, specifically by doping miRt into the mRNA sequence to inhibit mRNA expression in other non-targeted cells.

In summary, in order to enhance the expression of target mRNAs in target cells/tissues/organs and to reduce off-target effects, Moderna disclosed an mRNA sequence design strategy in patent WO2022/266083: including a target mRNA sequence, a regulatory sequence encoding inhibitor protein doped with miRNAs, which can indirectly regulate target mRNA expression in target organs by adjusting the expression of inhibitor protein in both target and non-target tissues. CureVac adjusted the expression of the target protein in non-target tissues, thereby indirectly regulating the expression of the target mRNA in the target organ.

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