Non-viral gene delivery systems for osteoarthritis therapy.

Osteoarthritis (OA) is a degenerative joint disease marked by periarticular bony overgrowth and the degradation of articular cartilage, leading to severe pain, impaired joint function, and reduced quality of life for those affected. Current OA treatments, including pharmacotherapy, physical therapy, and joint replacement surgery, often provide limited therapeutic benefits and are associated with various side effects. As a result, there is a pressing need for alternative treatment options. Gene therapy has emerged as a promising approach for achieving longer-lasting benefits by repairing or modulating the molecular and cellular mechanisms within the joint. Specifically, gene therapy for OA involves either suppressing the expression of detrimental genes or enhancing the expression of therapeutic genes. The success of these approaches, however, significantly depends on the safe and efficient delivery platforms used. Given the risks of insertional mutations and high production costs associated with viral vectors, considerable efforts have been made to develop non-viral systems as safer and more cost-effective alternatives for gene delivery. Over the past few decades, a variety of innovative non-viral vectors with integrated functions have been proposed, successfully overcoming the challenges of gene delivery. The substantial progress made in the rational design of these vectors, along with their enhanced performance in OA gene therapy, warrants a comprehensive and timely review. This article aims to summarize these advancements, starting with a discussion of representative therapeutic gene targets for OA treatment. We then review the innovative non-viral vectors used in OA gene therapy, including lipids, extracellular vesicles, natural and synthetic polymers, inorganic nanoparticles, and protein/peptide carriers. Finally, we address key aspects that need further optimization to facilitate the design of non-viral vectors and promote their therapeutic application in OA treatment.