Rheumatoid arthritis (RA) is an autoimmune disease characterised by inflammation of the joints, leading to pain, swelling, stiffness and eventually joint and bone damage. This results from the infiltration of immune cells, such as T cells, B cells and macrophages, into synovial tissue, which comprises membranes that line joint cavities and tendons.

First-line treatment of RA typically involves non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. In severe cases, disease-modifying antirheumatic drugs (MDARD) such as methotrexate (MTX) or anti-TNF-α monoclonal antibodies (mAbs), may be used to slow the progression of the disease. However, no option is curative, and patients receiving MDARDs face the additional burden of severe side effects like liver toxicity.

Now, a potential treatment option has been described by Professor Shawn Chen Xiaoyuan from NUS Biomedical Engineering, NUS Medicine and NUS Chemical and Biomolecular Engineering, where cell signalling molecules known to activate programmed cell death are delivered to immune cells within synovial tissue via an emerging nanotechnology-based method known as DNA-origami. Together with Prof Zhen Yang (Fujian Normal University), Dr Jie Chao (Nanjing University of Posts and Telecommunications) and Dr Ling Li (Sichuan University), DNA scaffolds are designed to deliver and present signalling molecules to their receptor molecules on immune cells in inflamed joints. This work, which showed a reduction in inflammation post treatment in in vivo models was described in Nature Materials in April 2024.

Designer DNA origami for nanodevice therapeutic delivery

DNA origami is an emerging technique that involves folding DNA into precise nanoscale two-dimensional (2D) or three-dimensional (3D)-shapes. These can then be used as scaffolds to carry molecules whose functionality is dependent on a precise spatial arrangement.

In their work, Prof Chen’s team fabricated a 2D scaffolding structure from a DNA origami nanosheet, upon which the cell signalling ligand CD95L was arranged in a precise hexagonal pattern with 10 nm intermolecular spacing, mimicking their natural arrangement in the body.

In vivo, CD95L binds to and activates CD95 and this in turn initiates programmed cell death. It is proposed that if CD95 signalling pathway could be activated in the immune cells responsible for synovial inflammation, then inflammation would subside thus providing relief for RA sufferers.

To better control the activation of CD95 signalling, the team added DNA-based fasteners to the DNA origami, which allowed it to roll into a tube-shaped nanodevice, effectively wrapping the CD95L within the cylindrical structure. The fasteners then allowed the nanodevice to open in response to a change in acidity. In healthy tissues with neutral conditions (pH ~7.4), the DNA origami nanodevice remains closed, shielding the CD95L array inside. At the inflamed joints where the pH is typically more acidic (pH: 6.5), the nanodevice will open up, exposing the CD95L array.

The advantage of their design over conventional intravenous administration of soluble CD95L lies in the cylindrical structure, which serves to protect CD95L until it reaches the inflamed site. In the in vivo model used in their study, the DNA origami nanodevice was found to successfully activate CD95 signalling in the inflamed synovial tissue, while sparing healthy tissues in the liver. Liver damage was therefore not observed. There were also significantly reduced levels of circulating inflammatory molecules, indicating a reduction in inflammation.

Combined, these results demonstrate how designer DNA origami can be used to precisely control cellular signalling, offering a promising approach for developing targeted cell signalling-based treatments for RA and certain cancers .