Degeneration of articular cartilage at joint surfaces due to age, injury, or disease (e.g., osteoarthritis) causes significant pain, disability and decreased quality of life. Current treatments fail to effectively repair damaged cartilage and typically only delay the degeneration that leads to osteoarthritis and the need for joint replacement. In osteoarthritis, joint degeneration creates a proinflammatory environment that reduces cell anabolic activity and promotes pathological catabolic and senescent cell phenotypes, which in turn promote further tissue degeneration. This proinflammatory signalling drastically limits the effectiveness of current osteoarthritis treatments and is a major cause of loss of function and pain in the disease. Advanced biomaterials and gene delivery have the potential to promote neocartilage formation, restore tissue functionality and the regenerative capacity of osteoarthritic cells. However, biomaterial approaches have had limited success due to the complex zonal structure of cartilage and difficulties providing regenerative environments while supporting load bearing. The proposed project will build on the applicant’s experience in functionalised biomaterial design to overcome these issues. To achieve this, a tri-layered, load-bearing scaffold mimicking the collagen architecture and zonal mechanical properties of cartilage will be constructed through combined fused deposition modelling (FDM) and melt electrowriting (MEW). This will be integrated with corresponding tri-layered hydrogels, optimised to promote zone-specific cartilage regeneration. The layers of this construct will be functionalised to non-virally deliver corresponding plasmids expressing anti-inflammatory small interfering (si)RNA and a zone-specific anabolic gene to promote cartilage regeneration. The ability of the proposed construct to attenuate inflammatory signalling, promote zone-specific chondrocyte anabolism to repair critical sized cartilage defects and halt degenerative processes will be investigated in vitro and in a preclinical animal model. This approach has the potential to revolutionise treatment of osteoarthritis while providing an adaptable platform applicable to degenerative conditions in other tissues.