<(From Left) Dr. Subin Yoon, Ph.D candidate Hyeonggon Cho, Prof. Jae-Hwan Nam, Prof. Young-suk Lee>
Since the COVID-19 pandemic, mRNA vaccines have gained attention as a next-generation pharmaceutical technology. mRNA therapeutics work by delivering genetic instructions that enable cells to produce specific proteins for therapeutic effects. However, their efficacy has been reported to decline in elderly individuals or patients with obesity. To address this limitation, Korean researchers have newly designed a key regulatory region of mRNA that improves therapeutic protein production efficiency, developing a next-generation mRNA platform that maintains effectiveness even in aging and obesity conditions.
KAIST (President Kwang Hyung Lee) announced on the 10th of March that a joint research team led by Professor Young-suk Lee of the Department of Bio and Brain Engineering and Professor Jae-Hwan Nam of The Catholic University of Korea (President Jun-Gyu Choi) has developed a new mRNA platform by precisely designing the sequence of the 5′ untranslated region (5′UTR)*, a key regulatory region of mRNA.
*5′ untranslated region (5′UTR): A region of mRNA that initiates and regulates protein production. The design of this region influences both the amount and speed of protein synthesis.
The research team analyzed large-scale bioinformatics datasets to identify 5′UTR sequences that enable proteins to be produced more efficiently across diverse cellular environments. When applied, the designed sequences significantly enhanced protein production and immune responses even in preclinical models of aging and obesity.
mRNA is a long single-stranded RNA molecule that serves as the blueprint for producing proteins required by the body. It consists of several components: the 5′UTR, which initiates and regulates the rate of protein production; the coding sequence (CDS), which contains the genetic information for a specific protein; the 3′ untranslated region (3′UTR), which helps maintain mRNA stability within cells; and the poly(A) tail, which further enhances stability and supports protein synthesis.
Among these components, the 5′UTR and 3′UTR do not determine the type of protein produced, but they play a critical role in regulating how efficiently the protein is synthesized. For this reason, these regions are receiving increasing attention as key bioengineering platforms for improving the performance of various mRNA therapeutics, including vaccines and treatments.
To identify highly efficient 5′UTR sequences capable of promoting protein production across multiple tissues and cellular environments, the team conducted an integrated analysis of large-scale biological datasets. This included multiple analytical approaches such as RNA sequencing (RNA-seq) for analyzing gene activity across tissues, single-cell RNA sequencing (scRNA-seq) for examining gene expression at the individual cell level, and ribosome profiling (Ribo-seq) for measuring actual protein translation efficiency.
The researchers also focused on the fact that in aging or obesity conditions, cells often experience high levels of stress—particularly oxidative stress—which can reduce their ability to synthesize proteins. When the newly designed mRNA therapeutics were applied to preclinical models of aging and obesity, the results showed significantly improved protein production and immune responses compared with existing approaches. This research is expected to be applicable not only to mRNA vaccines but also to a wide range of biopharmaceutical technologies, including gene therapies and immunotherapies.
Professor Young-suk Lee of KAIST Department of Bio and Brain Engineering stated, "This study identified a design strategy that enables mRNA to produce proteins more efficiently by analyzing large-scale biological data," adding, "This technology will provide an important foundation for ensuring that mRNA vaccines and therapeutics remain effective even in environments where drug efficacy may decline, such as in elderly or obese patients."
In this study, Dr. Subin Yoon from The Catholic University of Korea and doctoral candidate Hyeonggon Cho from KAIST participated as co-first authors. The research findings were published online on January 2 in the internationally renowned journal Molecular Therapy (IF = 12.0), a leading journal in gene and cell therapy.
(Paper title: "Designing 5′UTR sequences improves the capacity of mRNA therapeutics in preclinical models of aging and obesity" DOI: https://doi.org/10.1016/j.ymthe.2025.12.060)
This research was supported by the Excellent Young Researcher Program and the Bio-Medical Technology Development Program of the National Research Foundation of Korea funded by the Ministry of Science and ICT, the Infectious Disease Response Innovative Technology Support Program of the Ministry of Food and Drug Safety, and the Infectious Disease Prevention and Therapeutics Technology Development Program of the Korea Health Industry Development Institute.
