Osteoarthritis (OA) is a chronic, debilitating disease that substantially impairs the quality of life of affected individuals. The underlying mechanisms of OA are diverse and are becoming increasingly understood at the systemic, tissue, cellular and gene levels. However, the pharmacological therapies available remain limited, owing to drug delivery barriers, and consist mainly of broadly immunosuppressive regimens, such as corticosteroids, that provide only short-term palliative benefits and do not alter disease progression. Engineered RNA-based and cell-based therapies developed with synthetic chemistry and biology tools provide promise for future OA treatments with durable, efficacious mechanisms of action that can specifically target the underlying drivers of pathology. This Review highlights emerging classes of RNA-based technologies that hold potential for OA therapies, including small interfering RNA for gene silencing, microRNA and anti-microRNA for multi-gene regulation, mRNA for gene supplementation, and RNA-guided gene-editing platforms such as CRISPR–Cas9. Various cell-engineering strategies are also examined that potentiate disease-dependent, spatiotemporally regulated production of therapeutic molecules, and a conceptual framework is presented for their application as OA treatments. In summary, this Review highlights modern genetic medicines that have been clinically approved for other diseases, in addition to emerging genome and cellular engineering approaches, with the goal of emphasizing their potential as transformative OA treatments.

骨关节炎 (OA) 是一种慢性、使人衰弱的疾病，严重损害受影响个体的生活质量。OA 的潜在机制多种多样，并且在系统、组织、细胞和基因水平上的理解日益深入。然而，由于药物输送障碍，可用的药物疗法仍然有限，并且主要由广泛的免疫抑制疗法组成，例如皮质类固醇，其仅提供短期姑息益处并且不能改变疾病进展。利用合成化学和生物学工具开发的基于 RNA 和细胞的工程疗法为未来的 OA 治疗提供了希望，其持久、有效的作用机制可以专门针对病理学的潜在驱动因素。本综述重点介绍了具有 OA 治疗潜力的基于 RNA 的新兴技术，包括用于基因沉默的小干扰 RNA、用于多基因调控的 microRNA 和抗 microRNA、用于基因补充的 mRNA 以及 RNA 引导的基因编辑平台，例如如 CRISPR-Cas9。还检查了各种细胞工程策略，以增强疾病依赖性、时空调节的治疗分子的产生，并提出了它们作为 OA 治疗应用的概念框架。总之，除了新兴的基因组和细胞工程方法之外，本综述还重点介绍了已被临床批准用于其他疾病的现代基因药物，目的是强调它们作为变革性 OA 治疗的潜力。