Nature publication explains mechanisms of mRNA-based therapeutics in study from Polish researchers

WARSAW, Poland, April 16, 2025 — Researchers from the International Institute of Molecular and Cell Biology in Warsaw (IIMCB) described a new mechanism that improves the efficiency of mRNA-based therapies. The research findings will facilitate the development of novel therapeutics against cancers and infectious diseases. The scientific experiments were carried out at IIMCB, but important contributions also came from collaborators at the Faculty of Physics and Faculty of Biology of the University of Warsaw, the Medical University of Warsaw, and the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences. The breakthrough study by the Polish researchers has just been published in Nature. 

"mRNA vaccines played a key role in controlling the spread of the pandemic. However, mRNA itself is an exceptionally unstable molecule. This does not affect the safety of the therapy but limits its effectiveness—for example, by shortening the duration of action. A particularly important role in mRNA stability is played by its so-called poly(A) tail. In our research, we examined these limitations," says Prof. Andrzej Dziembowski from the Laboratory of RNA Biology – ERA Chairs Group at the International Institute of Molecular and Cell Biology in Warsaw, one of the lead authors of the study.

His team analyzed the anii-COVID-19 vaccines, Comirnaty and Spikevax, widely used during the pandemic. Both operate similarly: they contain mRNA molecules carrying instructions for producing the S protein, present on the surface of the SARS–CoV–2 coronavirus.

"The mRNA present in vaccines works just like the natural mRNA from our cells. After intramuscular administration, the vaccine’s mRNA reaches immune cells, which produce the S protein. Our body learns to recognize it. Thus, if we later encounter the real virus, our organism will be ready to react and prevent the disease," says Dr. Seweryn Mroczek from IIMCB and the University of Warsaw.

As the researchers explain, each mRNA molecule has a poly(A) tail at its end. It is essential for mRNA stability and effective protein production. "We decided to take a closer look at these tails," adds Dr. Seweryn Mroczek. "We wanted to understand how poly(A) tails change during the vaccine’s action," summarizes the scientist.

The researchers used modern technology called nanopore sequencing, which allowed direct reading of sequences of vaccine mRNA molecules, including the poly(A) tails.

"We created specialized software to analyze sequencing data from therapeutic mRNA molecules, focusing on poly(A) tail metabolism," adds Dr. Paweł Krawczyk from Prof. Andrzej Dziembowski's research group, who was responsible for computational methods.

TENT5A – a time machine for mRNA

A team of Polish researchers from the International Institute of Molecular and Cell Biology in Warsaw collaborated with scientists from other research units from the Ochota Campus. This Warsaw-based scientific hub hosts some of Poland’s most prominent research institutes and academic institutions. The team was the first in the world to describe the crucial role of the enzyme TENT5A in extending the aforementioned poly(A) tails of therapeutic mRNA molecules. Until now, it was assumed that the poly(A) tail of mRNA therapeutics could only be shortened. Extending it is like flipping over an hourglass—it ‘buys’ extra time, allowing the mRNA to function significantly longer in cells," explains Dr. Paweł Krawczyk.

The enzyme TENT5A is naturally present in certain cells of our body. Its role is to add building blocks to the mRNA’s poly(A) tail.

"We have demonstrated that TENT5A makes mRNA molecules more stable, enabling longer-lasting and more effective production of antigens—substances that trigger the body’s immune response," clarifies Dr. Krawczyk.

"Stabilization of mRNA molecules by the TENT5A enzyme is a mechanism that has been poorly understood so far, yet it is universal. It holds enormous potential for medicine, as extensive research is currently underway into various applications of mRNA as therapeutics," adds Prof. Dziembowski.

Macrophages – the key to vaccine effectiveness

The study also allowed researchers to understand which type of cells plays the most important role in the action of mRNA vaccines. Scientists have proved these to be macrophages. These immune cells are responsible for capturing and neutralizing "intruders." After vaccine administration, macrophages migrate to the injection site, take up mRNA carried in special lipid molecules, and subsequently produce the antigen encoded in them.

"Already in the early stages of our research, we observed that the poly(A) tail is extended in macrophages, but at that time we did not realize how crucial these cells were," says Dr. Seweryn Mroczek from the Laboratory of RNA Biology at IIMCB. "During the course of the study, we demonstrated that the absence of TENT5A in macrophages reduces vaccine efficacy," concludes Dr. Mroczek.

Researchers from the International Institute of Molecular and Cell Biology in Warsaw emphasize that despite the breakthrough findings described in Nature, knowledge about mRNA metabolism still requires deeper understanding. "In future studies within the Virtual Research Institute funded by the Polish Science Fund, we plan to use our discoveries to develop improved mRNA-based medicines," says Prof. Andrzej Dziembowski.

The groundbreaking research that led to the Nature publication was conducted using the IN-MOL-CELL Infrastructure of the International Institute of Molecular and Cell Biology in Warsaw. This infrastructure was purchased with funding from the National Recovery Plan.

As the researchers from IIMCB emphasize, the publication in Nature would not have been possible without the dedication and skills of all team members. The scientific experiments were carried out at IIMCB, but important contributions also came from collaborators at the University of Warsaw, the Medical University of Warsaw, and the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences.

The first such publication in the 21st century

Nature is considered the most prestigious scientific journal in the world. It is also one of the oldest, having been founded in 1869. The journal has the highest Impact Factor among multidisciplinary publications.

“Our path to publishing in Nature was long and challenging. We began work on the project during the pandemic, in mid-2021. After submitting the first version of the article in December 2022, we were asked multiple times to provide additional data and revise the manuscript. We are especially proud of the fact that this is the first publication in the life sciences to appear in Nature in the 21st century that was developed exclusively by Polish scientific institutions,” recalls Prof. Andrzej Dziembowski.

The results also inspired the creation of an innovative educational program. In the 2025/2026 academic year, the Faculty of Medicine at the University of Warsaw will launch a new master’s degree program—Biological Therapeutics. The International Institute of Molecular and Cell Biology is a co-founder of the program. It will train future professionals in biotechnology, biological drugs, and mRNA-based therapies.

The scientific article “Re-adenylation by TENT5A enhances efficacy of SARS–CoV–2 mRNA vaccines” is available at: https://www.nature.com/articles/s41586-025-08842-1

Authors of the article:

Paweł S. Krawczyk – International Institute of Molecular and Cell Biology (IIMCB)

Michał Mazur – International Institute of Molecular and Cell Biology (IIMCB)

Wiktoria Orzeł – University of Warsaw, Faculty of Biology; International Institute of Molecular and Cell Biology (IIMCB)

Olga Gewartowska – International Institute of Molecular and Cell Biology (IIMCB)

Sebastian Jeleń – International Institute of Molecular and Cell Biology (IIMCB); University of Warsaw, Faculty of Biology

Wiktor Antczak – International Institute of Molecular and Cell Biology (IIMCB); University of Warsaw, Faculty of Biology

Karolina Kasztelan – International Institute of Molecular and Cell Biology (IIMCB)

Aleksandra Brouze – International Institute of Molecular and Cell Biology (IIMCB); University of Warsaw, Faculty of Biology

Katarzyna Matylla-Kulińska – International Institute of Molecular and Cell Biology (IIMCB); University of Warsaw, Faculty of Biology

Natalia Gumińska – International Institute of Molecular and Cell Biology (IIMCB)

Bartosz Tarkowski – International Institute of Molecular and Cell Biology (IIMCB)

Ewelina P. Owczarek – International Institute of Molecular and Cell Biology (IIMCB)

Kamila Affek – International Institute of Molecular and Cell Biology (IIMCB)

Paweł Turowski – ExploRNA Therapeutics

Agnieszka Tudek – Institute of Biochemistry and Biophysics PAS

Małgorzata Sroka – International Institute of Molecular and Cell Biology (IIMCB)

Tomasz Śpiewla – Faculty of Physics, University of Warsaw

Monika Kusio-Kobiałka – International Institute of Molecular and Cell Biology (IIMCB)

Aleksandra Wesołowska – Department of Medical Biology, Medical University of Warsaw

Dominika Nowis – Laboratory of Experimental Medicine, Medical University of Warsaw

Jakub Gołąb – Department of Immunology, Medical University of Warsaw

Joanna Kowalska – Faculty of Physics, University of Warsaw

Jacek Jemielity – Centre of New Technologies, University of Warsaw

Andrzej Dziembowski – International Institute of Molecular and Cell Biology (IIMCB); Faculty of Biology, University of Warsaw

Seweryn Mroczek – Faculty of Biology, University of Warsaw; International Institute of Molecular and Cell Biology (IIMCB)

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ABOUT IIMCB

The International Institute of Molecular and Cell Biology in Warsaw (IIMCB) is a unique Polish research institution established under an international agreement between UNESCO and the Government of the Republic of Poland. The Institute conducts research in the fields of RNA and cell biology, aiming to understand the molecular basis of human diseases and to support the development of innovative therapeutic and diagnostic methods.

IIMCB holds the highest scientific classification (A+) awarded by the Polish Ministry of Science and Higher Education and is a member of EU-LIFE, an alliance of leading European life sciences research institutes. The Institute is currently implementing the RACE project, funded by the European Commission, with the goal of becoming a world-class Centre of Excellence in RNA and Cell Biology. Through this initiative, IIMCB aims to combine outstanding scientific achievements with cutting-edge technologies and professional commercialization activities.

 

 

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