While mRNAs mediate the production of certain good / protective proteins, antisense oligonucleotides such as small inhibitory RNA (siRNA) can be used for blocking the production of bad / harmful proteins. RNA medicines are safer than other forms of gene therapy as they do not induce permanent changes in the DNA where all our genetic information is stored.

However, both mRNAs and siRNAs are very unstable molecules and have a short life span in our body. Together with stability, another major problem associated with siRNAs is their availability inside cells. Once we treat the diseased cells with siRNAs, they get trapped inside small compartments (called endosomes), and may not be able to escape and block the harmful proteins. To overcome these issues, one solution is to increase the stability and availability of siRNAs by modifying them chemically. Chemical modifications are a few changes in the structure of these molecules which enables us to attach completely different molecules to it. We utilize these modifications to make strong bonds with molecules that can solve the problems that we face in siRNA therapy.

Another way to help protect RNAs from degradation and improve the duration of the therapeutic effects is to encapsulate them into ‘delivery vehicles’. In that sense, we are developing nanoparticles (structures smaller than one millionth of a meter) for delivery of mRNA and/or siRNA to cartilage cells and tissues. These nanoparticles are made of a polymeric material safe to use in humans which can increase the stability of the RNAs in our body after injection, serving as an excellent delivery vehicle for joint diseases. Here we plan to improve the chemical properties of polymeric nanoparticles to deliver RNAs more efficiently into cartilage cells. We also investigate the mechanism by which they are taken up by cells and release the RNA for production of protective and repair proteins. Besides, it is possible to modify the surface of these nanoparticles, which may enhance cartilage penetration and success of treatments.

Altogether, we plan to use the outcomes from these research projects to optimize the delivery of RNA therapeutics and the regulation of genes involved in cartilage degeneration. Together with other collaborators from CARTHAGO, these approaches (delivery vehicles and chemical modifications of RNAs) will be available for delivery to more complex models, such as tissue and organ cultures. In a later stage, they will finally be tested for cartilage repair in tissue, organs and animal models of the disease. In the end, the goal is to make these delivery systems with RNA therapeutics available for clinical trials involving humans.