Chemists at the National University of Singapore (NUS) have come up with a new approach using disulfide-containing small molecules to control and deliver ribonucleic acid (RNA) in a reversible manner. The research team combined post-synthetic RNA acylation chemistry with dynamic disulfide exchange reaction to create a method for regulating the activity and delivery of RNA. This allows the RNA molecule to be disguised and its activity and delivery can be controlled until it reaches its target site within the cell.A new approach has been developed to use disulfide-containing small molecules to control and deliver RNA in a reversible manner. This strategy aims to overcome the challenges associated with RNA delivery, which has been a major obstacle in the field of RNA-based therapeutics. Despite the widespread use of lipid nanoparticles for RNA delivery, including the distribution of COVID-19 mRNA vaccines, they have limitations in terms of their effectiveness and safety. Therefore, there is a need for alternative methods to address these limitations. Assistant Professor and his research team are leading the way in exploring this new strategy.ZHU Ru-Yi from the NUS Department of Chemistry has created a technique that utilizes a chemical process called post-synthetic RNA acylation chemistry, and combined it with dynamic disulfide exchange reaction for RNA delivery and reversible control. This technique allows for the hiding of the RNA molecule, giving researchers the potential to control its activity and delivery until it reaches its intended location within the cell.
The findings of the study were printed in the publication Angewandte Chemie International Edition on 13 March 2024.
The team discovered that by incorporating specific chemical markers consisting of disulfide-contTraining RNA with these groups can inhibit the catalytic activity and folding of RNA, temporarily concealing the instructions. Then, when necessary, the RNA can be activated by removing these markers, allowing cells to once again read and act on the instructions. This approach enables RNA to quickly enter cells, distribute efficiently, and become active in the cell’s cytosol without being trapped in lysosomes. The researchers believe that their method will be accessible to laboratories involved in RNA biology and has the potential to be a versatile platform for RNA-based applications.
Assistant Professor Zhu stated, “Our research demonstrates the first example of this novel strategy.”The study focused on a new method for delivering RNA into cells using only small molecules. The researchers believe that their approach will attract more interest from other scientists looking to improve the method and will have applications in the field of RNA biology and biomedicines. They are also working on developing new strategies to modify RNA and enhance RNA-based therapeutics.
