Targeting Osteoarthritis with Nano-Ghosts System Entrapping RNA Interference Molecules

Osteoarthritis (OA) is the leading cause of joint disabilities and is characterized by articular cartilage degradation, subchondral bone thickening and synovial inflammation. Current OA management is largely palliative, putting disease modifying treatments in high demand. In recent years, RNA interference (RNAi) technologies have been suggested as a promising approach for treating many diseases, including OA. Nonetheless, the clinical use of RNAi molecules is hindered by the lack of safe and efficient vectors. Our lab has developed an innovative delivery platform, termed Nano-Ghosts (NGs), which is based on nano-vesicles reconstructed from the plasma membrane of mesenchymal stem cells (MSCs). The NGs were shown to retain MSC membrane proteins and targeting capabilities towards sites of inflammation, like osteoarthritic tissue. Our goal in this project is to develop targeted NG-RNAi formulation for treating OA, focusing on the silencing of microRNA 221 (miR-221), a negative regulator of chondrogenesis. In particular, we aim to investigate the effect of our formulation on chondrogenesis as well as demonstrate the NGs’ safety and efficacy in preclinical OA models. Our results so far show that electroporation can be applied to load the NGs with locked nucleic acid miR-221 inhibitor, with an efficiency of 30%. Such NGs were readily taken up by MSC in vitro showing active targeting at 30 minutes of incubation, demonstrated by confocal microscopy, leading to significant miR-221 silencing, which is expected to induce chondrogenesis. Future experiments will aim to investigate the translational potential of the NG system for treating joint inflammation and cartilage defects using in vivo animal models.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No 642414