Osteoarthritis (OA) is a chronic, debilitating disease that significantly impairs quality of life. Current treatments are limited, with pharmacological options mainly being broadly immunosuppressive and providing only short-term relief. Engineered RNA-based and cell-based therapies offer promising approaches for durable, targeted treatments. This review highlights emerging RNA-based technologies, including small interfering RNA (siRNA), microRNA (miRNA), and anti-microRNA, as well as cell-engineering strategies for disease-modifying OA therapies. RNA-guided gene-editing platforms like CRISPR-Cas9 are also discussed. The review emphasizes the potential of these technologies to transform OA treatment by targeting underlying disease mechanisms. Challenges include overcoming cartilage avascularity, synovial fluid recycling, and the hostile joint environment. Advances in RNA delivery and cell engineering are crucial for effective OA therapies. RNA-based therapies, such as siRNA and mRNA, have shown clinical promise, while CRISPR-Cas9 gene editing offers precise modifications. Cell therapies, including genetically engineered cells, can provide sustained, localized therapeutic effects. The review discusses various strategies for RNA delivery, including chemical modifications and specialized carriers, and highlights the potential of RNA-based and cell-based therapies in OA treatment. The integration of synthetic biology and gene editing is key to developing effective, targeted OA therapies.Osteoarthritis (OA) is a chronic, debilitating disease that significantly impairs quality of life. Current treatments are limited, with pharmacological options mainly being broadly immunosuppressive and providing only short-term relief. Engineered RNA-based and cell-based therapies offer promising approaches for durable, targeted treatments. This review highlights emerging RNA-based technologies, including small interfering RNA (siRNA), microRNA (miRNA), and anti-microRNA, as well as cell-engineering strategies for disease-modifying OA therapies. RNA-guided gene-editing platforms like CRISPR-Cas9 are also discussed. The review emphasizes the potential of these technologies to transform OA treatment by targeting underlying disease mechanisms. Challenges include overcoming cartilage avascularity, synovial fluid recycling, and the hostile joint environment. Advances in RNA delivery and cell engineering are crucial for effective OA therapies. RNA-based therapies, such as siRNA and mRNA, have shown clinical promise, while CRISPR-Cas9 gene editing offers precise modifications. Cell therapies, including genetically engineered cells, can provide sustained, localized therapeutic effects. The review discusses various strategies for RNA delivery, including chemical modifications and specialized carriers, and highlights the potential of RNA-based and cell-based therapies in OA treatment. The integration of synthetic biology and gene editing is key to developing effective, targeted OA therapies.