PT - JOURNAL ARTICLE AU - Nakanishi, Hideyuki AU - Itaka, Keiji TI - Extracellular ligand-responsive translational regulation of synthetic mRNAs using engineered receptors AID - 10.1101/2024.09.27.615322 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.09.27.615322 4099 - http://biorxiv.org/content/early/2024/10/01/2024.09.27.615322.short 4100 - http://biorxiv.org/content/early/2024/10/01/2024.09.27.615322.full AB - mRNA drugs can encode any protein and are regarded as a promising therapeutic modality. However, current mRNA drugs are not designed to enable conditional translation, although disease states and appropriate therapeutic protein levels can fluctuate. As extracellular biomolecules can serve as disease markers, in this study, we developed an extracellular ligand-responsive translational regulation system. This system consists of a tobacco etch virus protease (TEVp)-fused receptor and TEVp-sensitive translational regulator, which releases target mRNAs upon detecting disease markers such as arginine vasopressin, prostaglandin E2, and bradykinin. Furthermore, both translational upregulation and downregulation were achieved by changing the design of the target mRNA. Finally, we succeeded in suppressing the inflammatory signal through the translational upregulation of an anti-inflammatory protein. This system will pave the way for the next generation of mRNA therapy that enables disease state-matched production of therapeutic proteins.Competing Interest StatementTokyo Medical and Dental University has applied for a patent regarding the extracellular ligand-responsive translational regulation system.