Enhancement of Therapeutic mRNA Translation in Cellular Stress Conditions

This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of therapeutic proteins for the treatment of cancer, genetic disorders, and inflammatory diseases. The efficacy of mRNA-based gene therapy is strongly influenced by sequence design, chemical modifications, and structural features. Evidence shows that rational mRNA engineering can significantly enhance translation efficiency even under stress conditions that impair canonical protein synthesis, as observed in many pathological states. Cellular stress activates regulatory pathways that suppress global translation; however, optimized mRNA constructs can partially bypass these inhibitory mechanisms, enabling sustained protein expression. By improving mRNA stability and resistance to stress-responsive translational control, robust therapeutic protein production can be achieved even in challenging cellular environments. This article was prepared as a narrative review focused on translational regulation mechanisms relevant to therapeutic mRNA design under cellular stress conditions. Literature was collected from PubMed, Google Scholar, and Web of Science using keywords including "mRNA therapeutics," "cellular stress," "translation regulation," "UTR engineering," and "cap-independent translation." Studies published mainly between 2010 and 2025 were considered. Original articles and reviews related to stress-responsive translation and therapeutic mRNA optimization were included, while studies outside the scope of translational control and mRNA engineering were excluded. Priority was given to recent and mechanistically relevant publications.