Restoring pre-osteoarthritis cartilage matrix integrity via Col9 mRNA halts osteoarthritis progression

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by the progressive breakdown of cartilage. Here, we sought to define a pre-osteoarthritis (pre-OA) state using nanoindentation-based mechanical testing and evaluation of collagen organization in cartilage matrix. The reductions in elastic modulus and impaired viscoelasticity preceded any overt histological degeneration. This mechanical dysfunction was primarily driven by early disorganization of type II collagen, occurring before substantial depletion of cartilage components. We subsequently identified type IX collagen (Col IX), which played a critical role at the pre-OA stage. Intra-articular administration of Col9 mRNAs delivered by polymer-based nanomicelle restored pre-OA cartilage to a healthy, native-like collagen network architecture and preserved cartilage mechanical integrity, ultimately halting OA progression in the rat model. These findings identify viscoelastic dysfunction as an early biomechanical hallmark of pre-OA cartilage and establish Col9 mRNA as a potential anti-OA drug to prevent its onset. Together, these results provide a translatable framework in which quantitative mechanical-ultrastructural metrics guide ultra-early, presymptomatic intervention for degenerative diseases.