Gene Therapy for Osteoarthritis: Viral and Non-Viral Delivery Strategies

Osteoarthritis (OA) is the most prevalent joint disease, which is pathologically characterized by articular cartilage degradation, chronic synovial inflammation, subchondral bone remodeling, and osteophyte formation. Patients with OA suffer from joint pain, deformity, and functional impairment. Current therapies provide symptomatic relief but fail to halt or reverse disease progression. Gene therapy is being investigated for cartilage repair and modulation of intra-articular inflammation, with the aim of modifying disease progression. This narrative review summarizes the recent advances in viral and non-viral gene therapy approaches for OA, including therapeutic gene targets in preclinical and clinical trials. Potentially therapeutic genes can be injected into the joint cavity and transferred into specific joint tissue cells through viral vectors or non-viral carriers depending on the nature of transgenes, delivery materials, and targeting cells. Gene delivery to articular chondrocytes remains challenging as the cells are positioned in a dense extracellular matrix, while synovial fluid may further contribute to degradation or inactivation of delivered agents. Viral vectors, particularly adeno-associated virus (AAV), can support sustained transgene expression in joint tissues, although cartilage penetration efficiency remains to be improved. Non-viral carriers can deliver nucleic acids to synovial cells and, with suitable formulations, articular chondrocytes. Viral and non-viral delivery approaches may offer complementary benefits; integrating the advantages of both viral and non-viral platforms could potentially improve the efficacy and safety of gene therapy for OA. Finally, strategies to overcome translational barriers and future directions towards clinical applications are discussed.