Abstract

Osteoarthritis (OA) is a progressive and disabling joint disease driven by oxidative stress, chondrocyte senescence and extracellular matrix (ECM) degradation, yet lacks effective disease-modifying treatments. In this study, we identified miR-197-3p as a previously unrecognized, cartilage-protective miRNA significantly downregulated in both aged and osteoarthritic cartilage. Functional studies revealed that miR-197-3p restores ECM anabolism, suppresses senescence and directly targets G3BP1, a stress granule protein linked to redox imbalance and inflammatory signaling. To enable effective intra-articular delivery, we engineered a multifunctional microsphere platform (miR/PBNP@Gel) by co-encapsulating miR-197-3p and ultrasmall Prussian blue nanozymes (PBNPs) into GelMA hydrogel microspheres. This composite design synergistically enhances miRNA stability, facilitates cellular internalization and provides continuous reactive oxygen species (ROS) scavenging to protect mitochondrial function. miR/PBNP@Gel reversed mitochondrial dysfunction and senescence in OA chondrocytes, while promoting cartilage repair and joint function in vivo. Metabolomic profiling further revealed reprogramming of TCA cycle and antioxidant pathways. This work established miR-197-3p as a novel therapeutic regulator in OA and introduced a bioinstructive, injectable, and cell-free strategy that integrates miRNA therapy and redox modulation for disease modification and cartilage regeneration.