A KAIST-led team redesigned a key control region of mRNA using large-scale biological data, creating a next-generation platform that keeps protein production and immune responses strong even in aging or obese bodies, where standard mRNA drugs often lose potency.

Since the COVID-19 pandemic, mRNA vaccines have become one of medicine's most closely watched technologies. They work by delivering genetic instructions that tell a person's own cells to produce a specific protein, triggering a protective or therapeutic response. But the approach has a well-known blind spot; in older adults and people with obesity, cells often produce far less of the target protein, making mRNA drugs less effective.

A Korean research team, led by Professor Young-suk Lee of KAIST's Department of Bio and Brain Engineering and Professor Jae-Hwan Nam of the Catholic University of Korea, has proposed a new solution to this problem. The team re-engineered the 5′ untranslated region (5′ UTR) of mRNA, a short stretch that sits just ahead of the protein-coding sequence and acts like a volume dial for protein production, controlling how much protein gets made and how quickly.

Rather than relying on a single previously known sequence, researchers leveraged massive public biological datasets spanning multiple tissues and cell types. They investigated large-scale transcriptome data (RNA-seq), single-cell transcriptome data (scRNA-seq), and ribosome profiling data (Ribo-seq) to pinpoint 5′ UTR sequences that consistently enable strong protein output across diverse cellular environments.

The team paid particular attention to a condition common in aging and obesity: elevated oxidative stress, which puts cells under strain and can dampen their protein-making machinery. When the newly designed mRNA was tested in preclinical models of aging and obesity, it produced significantly more protein and triggered a stronger immune response than earlier RNA designs.

“This study demonstrates how the integrative analyses of massive biological datasets can uncover new design principles for therapeutic mRNAs,” said Professor Young-suk Lee. “We hope these findings will provide an important foundation for expanding the reach of mRNA vaccines and therapeutics to populations that have often been overlooked, including older adults and individuals with obesity.”

Beyond vaccines, the platform could also be applicable to gene therapies and immunotherapies that rely on efficient protein production. The findings, with Dr. Subin Yoon of the Catholic University of Korea and Hyeonggon Cho, a KAIST doctoral candidate, as co-first authors, were published online on January 2 in Molecular Therapy (Impact Factor 12.7). The research was supported by Korea's National Research Foundation, the Ministry of Food and Drug Safety, and the Korea Health Industry Development Institute.