Osteoarthritis (OA) is associated with metabolic imbalance of articular cartilage and an increase of intracellular reactive oxygen species (ROS). Synergistic therapy based on the codelivery of ROS scavengers and antisense oligonucleotides (ASO) into chondrocytes has the potential to effectively treat OA. Here, we developed a novel biocompatible metal‐organic framework (MOF)‐encapsulated nanozyme/ASO delivery platform (miR/IrO2@ZIF‐8) for OA treatment. IrO2 nanoparticles with the catalytic activities of superoxide dismutase/catalase were synthesized using a hydrothermal method, resulting in excellent ROS scavenging performance. IrO2 was further loaded into zeolitic imidazolate framework‐8 (ZIF‐8) to maintain its catalytic efficacy and regulate its size, surface charge, and biocompatibility to enhance the therapeutic effect of the platform. As an effective ASO delivery carrier, the synthesized IrO2@ZIF‐8 exhibited high antagomiR‐181a loading and lysosomal escape capacity, enabling it to rebalance cartilage metabolism. In vitro experiments showed that miR/IrO2@ZIF‐8 could restore ROS levels, mitochondrial membrane potential, and lipid peroxidation in chondrocytes. At the same time, the expression levels of proinflammatory markers (IL‐1β, IL‐6, and COX‐2) as well as the extracellular matrix degrading enzymes (ADAMTS‐5 and MMP13) were downregulated, indicating effective antioxidant, anti‐inflammatory, and anticartilage degradation effects. Notably, miR/IrO2@ZIF‐8 was able to deliver IrO2 nanoparticles and antagomiR‐181a to the cartilage tissue at a depth of up to 1.5 mm, thus solving the problems of poor permeability and difficult retention of drugs in cartilage tissue. This further improves the synergistic therapeutic effect on OA by inhibiting cartilage degradation. The combination of MOF‐encapsulated IrO2 nanozymes with antagomiR‐181a has an excellent therapeutic effect on OA, offering a promising translational medicine paradigm.
