The development of treatments to restore damaged cartilage that can provide functional recovery with minimal risk of revision surgery remains an unmet clinical need. Gene therapy shows increased promise as an innovative solution for enhanced tissue repair. This DCU research collaboration proposes a novel mRNA-Scaffold method for repairing cartilage. Biomaterials offer some promise to treat common knee cartilage injuries. For example, biomimetic biomaterials such as a highly porous type I/II collagen-hyaluronic acid scaffold have proved to be effective in providing support during early bone formation while also providing a regenerative template for new tissue formation. However, when developing a scaffold biomaterial for cartilage repair, it is crucial to consider mesenchymal stem/stromal cells (MSC) may cause subsequent complications. The new proposed scaffold tackles this issue through delivery of an inhibitor targeting microRNA-221 (miR-221). The silencing of miR-221 in human MSCs using the miR-activated scaffold promotes an improved and more robust cell-mediated cartilage formation. In this study, the miR-activated scaffolds successfully transfect human MSCs with miR-221 cargo in a sustained and controlled manner for up to 28 days. This innovative miR-activated scaffold for the delivery of a miR-221 inhibitor demonstrates capability to improve chondrogenesis with promise to enhance cartilage defect repair.