Inhibiting synovial inflammation and promoting cartilage repair in rheumatoid arthritis using a matrix metalloproteinase-binding hydrogel

Originating from synovial tissue, matrix metalloproteinase-9 (MMP-9) is a key inflammatory factor that promotes the formation and invasion of synovial pannus, leading to cartilage matrix destruction in rheumatoid arthritis (RA). However, clinical trials of systemic use of MMP-9 inhibitors are not successful due to severe side effects. Thus, locally inhibiting MMP-9 may be an alternative in the treatment of RA. Herein, we developed MMP-9 binding peptide-functionalized copper sulfide nanoparticles (CuS-T NPs) and delivered them with light crosslinking chondroitin sulfate methacrylate (ChSMA) hydrogel. We found that the CuS NP-doped hydrogels could inhibit synovial inflammation. Specifically, the CuS-T/ChSMA hydrogel could rapidly bind to MMP-9, thereby inhibiting not only the invasion of RA fibroblast-like synoviocytes but also the polarization of inflammatory M1-type macrophages. The underlying mechanism involved the inhibition of the MAPK pathway. Moreover, ChSMA hydrogel provided a cartilage matrix-mimic microenvironment and synergistically promoted the generation of collagen-2 and aggrecan with CuS NPs. In an adjuvant-induced arthritis mouse model, the intra-articular injection of ChSMA/CuS-T hydrogel significantly alleviated synovial inflammation and accelerated cartilage repair without causing any side effects, killing two birds with one stone in RA therapy.