Wilhelmsson's research group

These so-called fluorescent base analogues (see reviews by us in QRB 2010 Fluorescent nucleic acid base analogues,and BJOC2018 Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications) have molecular properties that are optimal for being inserted into the natural DNA/RNA structure (Figure 1).

We can therefore use them to, on a very detailed level, understand more about essential processes in cells like replication, transcription, and translation, as well as be applied in studies of the uptake of RNA therapeutics into cells. Fundamental knowledge thereof is vital to comprehend cellular processes and errors that could occur in such processes and cause diseases.

Following the uptake of RNA therapeutics into cell

One of our lines of research focuses on understanding and improving the delivery and function of RNA therapeutics inside living cells. By developing advanced fluorescent base analogues and imaging tools, we track how therapeutic RNA molecules are internalized, trafficked, and how they lead to their effect in real time (Figure 2).

This allows us to reveal key biological barriers and design strategies that enhance cellular uptake, stability, and efficacy.

In collaboration with Margaret Holme and Fredrik Höök we also investigate how RNA is packaged into LNPs. 

Through this work, we aim to accelerate the development of next generation RNA medicines with higher precision and therapeutic impact.

Metabolic fluorescence labeling of RNA

Our group develops innovative metabolic fluorescence labeling strategies to visualize and study RNA inside living cells with high precision without further engineering of the cells. By supplying cells with specially designed fluorescent nucleotide analogues, we enable the incorporation of bright, photostable labels directly into newly synthesized RNA (Figure 3).

This allows us to track RNA production and localization in real time without disrupting natural cell function. Through these technologies, we aim to uncover fundamental principles of RNA biology and create powerful tools for both basic research and the development of RNA based therapeutics.

FRET to study nucleic acid conformation and conformational changes upon protein/drug interaction

Our group employs Förster Resonance Energy Transfer (FRET) to unravel the conformational landscapes of nucleic acids and how these structures change upon interaction with proteins, small molecules, or therapeutic agents. By designing precise donor–acceptor fluorescent probes for nucleic acids – which we have named interbase FRET probes - we can monitor distance changes at the sub-nanometer scale and follow structural transitions in real time (Figure 4).

This enables us to dissect mechanistic pathways, identify binding induced conformational shifts, and gain molecular level insight into how nucleic acids respond to biological partners and drug candidates.

Optical tweezers of nucleic acids

We are also involved in RNA and DNA nanotechnology where we use optical tweezers to study structure and dynamics of short DNAs and RNAs. We are interested in the forces that govern the 2D and 3D structure of DNA and RNA, as well as in their interactions with ligands and proteins.

In collaboration with Fredrik Westerlund we use DNA/RNA base analogues developed in our lab to locally modify the stability and structure of the system at hand (Figure 5).

Several of the fluorescent molecules in their phosphoramidite form, which have been developed by the group, are now distributed by the American company Glen Research Corp., and their triphosphate form are distributed by Jena Biosciences via LanteRNA (company founded by several group members).

Publications

Find our scientific work here: ‪L. Marcus Wilhelmsson‬ - ‪Google Scholar‬‬‬‬‬‬‬‬‬

Long-term collaborators and key colleagues outside Chalmers

• Prof. Morten Grøtli, Gothenburg University
• Prof. Tom Brown, Oxford University
• Prof. Yitzhak Tor, UCSD
• Prof. Steven Magennis, University of Glasgow
• Prof. Anita Jones, University of Edinburgh
• AstraZeneca: R&D, Gothenburg – Drs. Anders Dahlén and Malin Lemurell