Extracellular ligand-responsive translational regulation of synthetic mRNAs using engineered receptors

mRNA drugs can encode any protein and are regarded as a promising therapeutic modality. In this study, we developed a new mRNA system allowing extracellular ligand-responsive translational regulation. This system consists of three mRNAs, two of which encode components for detecting extracellular ligands, and the other encodes the protein of interest, with a binding motif on 5UTR for translational regulation. In the presence of ligand biomolecules such as arginine vasopressin (AVP) and prostaglandin E2 (PGE2), the translation level of the protein of interest is upregulated or downregulated in a ligand biomolecule concentration-dependent manner. We showed upregulation of anti-inflammatory signaling in response to an inflammatory mediator, PGE2, demonstrating that this system allowed production of the therapeutic proteins according to the disease site environment. This system will pave the way for the next-generation mRNA drugs that self-adjust their protein production levels in response to fluctuating disease states. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/615322v3_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1cbe28forg.highwire.dtl.DTLVardef@874f85org.highwire.dtl.DTLVardef@175e39borg.highwire.dtl.DTLVardef@b1faca_HPS_FORMAT_FIGEXP M_FIG C_FIG mRNAs encoding regulatory components (an engineered receptor and a translational regulator) and a target mRNA are co-transfected into mammalian cells. In the absence of the ligand, the target mRNA is translationally repressed by the translational regulator. The ligand induces engineered receptor-mediated degradation of the translational regulator protein, resulting in the translational activation of the target mRNA.