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KAIST Suppresses Side Effects of mRNA Therapeutics, Broadly Applicable Platform for Safer, Personalized Treatments
<(From Left) Professor Yong Woong Jun, Ph.D candidate Tae Ung Jeong, Ph.D candidate Jihun Choi>
mRNA, widely known from the COVID-19 vaccine, is not actually a “therapeutic agent,” but a technology that delivers the blueprint for functional proteins into the body so that induces therapeutic effects. Recently, its application has expanded to cancer and genetic disease treatments, but mRNA therapeutics have caused serious side effects such as pulmonary embolism, stroke, thrombosis, and autoimmune diseases because proteins are excessively produced all at once immediately after administration. Although technology to control the endogenous protein factory has been continuously needed, there had been no suitable solution.
KAIST (President Kwang Hyung Lee) announced on the 1st of December that Professor Yong Woong Jun’s research team in the Department of Chemistry has proposed a new strategy that can control the initiation timing and rate at which mRNA produces proteins. By using this method, the rate of protein production can be adjusted/personalized according to a patient’s condition, enabling safer treatment.
This technology is expected to serve as an important turning point in next-generation mRNA therapeutics, not only fundamentally reducing side effects of mRNA treatments but also enabling application to treatment areas requiring precise protein regulation such as stroke, cancer, and immune diseases.
For a protein to be produced, the cell’s “protein production machinery (ribosomes and initiation factors)” must attach to the mRNA blueprint and begin working. The research team focused on the fact that delaying this process even slightly can prevent the sudden surge of protein production.
Therefore, instead of using complex technologies, they developed a simple method in which intentionally slightly damaged DNA fragments are attached to mRNA. These DNA fragments act like a small “shield,” preventing the protein production machinery from immediately attaching to the mRNA and thereby gently slowing the initiation speed of protein production.
The damaged DNA used here is a safe biological material naturally recycled in the body and is very inexpensive. Because it only needs to be mixed with mRNA right before injection, it is suitable for real-world medical use.
As time passes, the body’s natural “repair enzymes” partially degrade the damaged DNA, and during this process, the structure attached to the mRNA is released, smoothly transitioning the protein production speed back to normal mode. As a result, the previous risk of proteins being explosively produced all at once is greatly reduced.
The research team confirmed that by adjusting the length and degree of damage of the DNA, they could precisely design when and how slowly protein production would begin. They also found that even when multiple types of mRNA are administered at once, the proteins can be produced sequentially in the desired order, meaning this method could innovate existing approaches that required multiple separate injections for complex treatments.
This technology was selected by KAIST as one of its “Future Promising Core Technologies” and was also introduced at the “2025 KAIST Techfair Technology Transfer Session.”
<A translation-control strategy based on DNA–mRNA hybrids. The damaged base (in red) is removed by a repair enzyme, after which the DNA and mRNA dissociate, allowing translation factors and ribosomes to bind and initiate protein translation>
Professor Yong Woong Jun said, “Biological phenomena are ultimately chemistry, so we were able to precisely control the protein production process through a chemical approach,” and added that “this technology not only enhances the safety of mRNA therapeutics but also provides a foundation for expanding into precision treatments tailored to various diseases such as cancer and genetic disorders.”
The results of this research, with Jihun Choi (KAIST, 3rd-year PhD student) and Tae Ung Jeong (KAIST, 1st-year PhD student) participating as co–first authors, were published on November 6 in Angewandte Chemie International Edition, one of the most prestigious journals in the field of chemistry.
※ Paper title: “Harnessing Deaminated DNA to Modulate mRNA Translation for Controlled and Sequential Protein Expression,” Authors: Jihun Choi (KAIST, co–first author), Tae Ung Jeong (KAIST, co–first author), and Yong Woong Jun (KAIST, corresponding author), among a total of 10 authors, DOI: 10.1002/anie.202516389
This study was supported by the National Research Foundation of Korea (NRF) through the Excellent Young Researcher Program.
2025.12.02 View 1594 -
KAIST Identifies Key to Slowing Aging via RNA Regulation... Unlocks Mechanism for Longevity
As aging progresses, the quality of DNA and proteins inside cells declines, known to be the cause of various degenerative diseases. However, the connection between aging and RNA has remained largely unexplored. Now, a Korean research team has discovered that a ribosome-associated quality control factor—PELOTA, a protein essential for eliminating abnormal mRNA—plays a central role in slowing aging and promoting longevity. This breakthrough is expected to provide a new direction for future therapeutic strategies targeting human aging and neurodegenerative diseases.
KAIST (President Kwang Hyung Lee) announced that a joint research team—led by Professor Seung-Jae V. Lee of the Department of Biological Sciences at KAIST and the Research Center for RNA-mediated Healthy Longevity, Professor Jinsoo Seo of Yonsei University (President Dong-Sup Yoon), and Professor Kwang-Pyo Lee of the Korea Research Institute of Bioscience and Biotechnology (KRIBB, President Suk Yoon Kwon) under the National Research Council of Science & Technology (NST, Chairman Yeung-Shik Kim—has discovered that the protein ‘PELOTA*’, which plays a key role in ribosome-associated quality control, regulates the pace of aging.
*PELOTA: A key protein in maintaining cellular translational homeostasis, responsible for detecting and resolving errors during mRNA translation by ribosomes.
Until now, RNA—particularly mRNA—has generally been regarded as a transient intermediary in protein synthesis. Its instability made it difficult to study quantitatively or track over time, leaving its physiological and functional roles relatively understudied compared to DNA.
Using C. elegans (a nematode widely used in aging research due to its short lifespan), the researchers first discovered that the ribosome-associated quality control factor PELOTA is essential for longevity. In particular, when PELOTA was overexpressed in normal nematodes, their lifespan was extended, suggesting that ribosome-associated quality control mechanisms involved in removing abnormal mRNA are necessary for promoting longevity.
The study also revealed that the ribosome-associated quality control system simultaneously regulates both the mTOR signaling pathway—which senses nutrient status or growth signals to control cell growth, protein synthesis, and autophagy, and plays a key role in aging and energy metabolism—and the autophagy pathway, the cellular cleanup and recycling system through which cells break down and reuse unnecessary or damaged components.
When PELOTA was deficient, the mTOR pathway became abnormally activated, and autophagy was suppressed—accelerating aging. Conversely, activation of PELOTA inhibited mTOR and induced autophagy, thereby maintaining cellular homeostasis and extending lifespan.
Notably, this mechanism was found to be conserved in both mice and humans. The study also showed that the loss of PELOTA could contribute to muscle aging and Alzheimer’s disease, suggesting its relevance to age-related disorders.
These findings indicate that the study of PELOTA and ribosome-associated quality control could play an important role in developing therapeutic strategies for human aging and neurodegenerative diseases.
Professor Seung-Jae V. Lee of KAIST, who led the research, stated, “While the connection between quality control and aging has been well established at the DNA and protein levels, molecular evidence showing that RNA quality control also functionally contributes to lifespan regulation has been very limited.” He emphasized that the “study provides strong evidence that the removal of abnormal RNA is a central axis in the aging regulatory network.”
The study was published on August 5th in the prestigious journal PNAS (Proceedings of the National Academy of Sciences), with Dr. Jongsun Lee and Dr. Eun Ji Kim of KAIST, Dr. Bora Lee of KRIBB, and Dr. Hyein Lee of Yonsei University as co-first authors.
※ Title: Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species ※ DOI: https://doi.org/10.1073/pnas.2505217122
This research was supported by the Global Leader Research Project of the National Research Foundation of Korea.
2025.08.18 View 3933 -
KAIST Team Develops Optogenetic Platform for Spatiotemporal Control of Protein and mRNA Storage and Release
<Dr. Chaeyeon Lee, Professor Won Do Heo from Department of Biological Sciences>
A KAIST research team led by Professor Won Do Heo (Department of Biological Sciences) has developed an optogenetic platform, RELISR (REversible LIght-induced Store and Release), that enables precise spatiotemporal control over the storage and release of proteins and mRNAs in living cells and animals.
Traditional optogenetic condensate systems have been limited by their reliance on non-specific multivalent interactions, which can lead to unintended sequestration or release of endogenous molecules. RELISR overcomes these limitations by employing highly specific protein–protein (nanobody–antigen) and protein–RNA (MCP–MS2) interactions, enabling the selective and reversible compartmentalization of target proteins or mRNAs within engineered, membrane-less condensates.
In the dark, RELISR stably sequesters target molecules within condensates, physically isolating them from the cellular environment. Upon blue light stimulation, the condensates rapidly dissolve, releasing the stored proteins or mRNAs, which immediately regain their cellular functions or translational competency. This allows for reversible and rapid modulation of molecular activities in response to optical cues.
< Figure 1. Overview of the Artificial Condensate System (RELISR). The artificial condensate system, RELISR, includes "Protein-RELISR" for storing proteins and "mRNA-RELISR" for storing mRNA. These artificial condensates can be disassembled by blue light irradiation and reassembled in a dark state>
The research team demonstrated that RELISR enables temporal and spatial regulation of protein activity and mRNA translation in various cell types, including cultured neurons and mouse liver tissue. Comparative studies showed that RELISR provides more robust and reversible control of translation than previous systems based on spatial translocation.
While previous optogenetic systems such as LARIAT (Lee et al., Nature Methods, 2014) and mRNA-LARIAT (Kim et al., Nat. Cell Biol., 2019) enabled the selective sequestration of proteins or mRNAs into membrane-less condensates in response to light, they were primarily limited to the trapping phase. The RELISR platform introduced in this study establishes a new paradigm by enabling both the targeted storage of proteins and mRNAs and their rapid, light-triggered release. This approach allows researchers to not only confine molecular function on demand, but also to restore activity with precise temporal control.
< Figure 2. Cell shape change using the artificial condensate system (RELISR). A target protein, Vav2, which contributes to cell shape, was stored within the artificial condensate and then released after light irradiation. This release activated the target protein Vav2, causing a change in cell shape. It was confirmed that the storage, release, and activation of various proteins were effectively achieved>
Professor Heo stated, “RELISR is a versatile optogenetic tool that enables the precise control of protein and mRNA function at defined times and locations in living systems. We anticipate this platform will be broadly applicable for studies of cell signaling, neural circuits, and therapeutic development. Furthermore, the combination of RELISR with genome editing or tissue-targeted delivery could further expand its utility for molecular medicine.”
< Figure 3. Expression of a target mRNA using the artificial condensate system (RELISR) in mice. The genetic material for the artificial condensate system, RELISR, was injected into a living mouse. Using this system, a target mRNA was stored within the mouse's liver. Upon light irradiation, the mRNA was released, which induced the translation of a luminescent protein>
This research was conducted by first author Dr. Chaeyeon Lee, under the supervision of Professor Heo, with contributions from Dr. Daseuli Yu (co-corresponding author) and Professor YongKeun Park (co-corresponding author, Department of Physics), whose group performed quantitative imaging analyses of biophysical changes induced by RELISR in cells.
The findings were published in Nature Communications (July 7, 2025; DOI: 10.1038/s41467-025-61322-y). This work was supported by the Samsung Future Technology Foundation and the National Research Foundation of Korea.
2025.07.23 View 3320