<p>mRNA drugs can encode any protein, making them a promising treatment modality. In the present study, we developed a novel mRNA system that enables extracellular ligand-responsive translational regulation. This system consists of three mRNAs—two that encode components responsible for detecting extracellular ligands and a third that encodes the protein of interest, featuring a binding motif in the 5′ UTR for translational regulation. In the presence of ligand biomolecules, such as arginine vasopressin (AVP) and prostaglandin E₂ (PGE₂), the protein of interest is translationally upregulated or downregulated in a concentration-dependent manner. We demonstrated that this system enhances anti-inflammatory signaling in response to the inflammatory mediator PGE₂, enabling therapeutic protein production based on the disease site environment. This self-regulatory mechanism may help mitigate the risk of both excessive therapeutic protein-mediated adverse effects and insufficient therapeutic efficacy. Furthermore, by modifying its receptor module to detect different disease markers, the system can be adapted for the treatment of various conditions. Our findings pave the way for the development of next-generation mRNA drugs that can achieve both high therapeutic efficacy and minimal adverse effects.</p>