Nanozyme-enhanced injectable hyaluronic acid-based hydrogel for the treatment of osteoarthritis

The progression of osteoarthritis (OA) is dramatically accelerated by excessive reactive oxygen species (ROS)-induced apoptosis of chondrocytes and the inflammatory response of synovial macrophages. In this study, we developed an injectable hydrogel with a catalase-mimicking nanozyme activity as a therapeutic agent for OA. In vitro experiments confirmed that the HA and peroxide-mimetic nanoenzyme-enhanced hydrogel, containing ε-polylysine/Mn1.8Co1.2O4 (ε-PLE/MnCoO) nanoparticles, continuously eliminated ROS and inflammatory cytokines while promoting the polarization of inflammatory macrophages (M1 phenotype) towards anti-inflammatory macrophages (M2 phenotype) in dysfunctional microenvironments. When used for intraarticular injections in OA models, the nanoenzyme-enhanced hydrogel effectively reduced oxidative stress by scavenging ROS and regulating the immune microenvironment. It resulted in a subsequent reduction in the expression of inflammatory factors, including MMP-13, TNF-α, IL-1β, and iNOS in both the synovium and joint fluid. Moreover, cartilage repair was enhanced by the promotion of COL-2 and SOX-9 expression in the cartilage tissue, whereas osteophyte formation in OA was reduced. This study introduced an innovative treatment strategy for the clinical management of OA, demonstrating its significant potential for application in treating OA. •The injectable HA and peroxide-mimetic nanoenzyme-enhanced hydrogel is capable of eliminating ROS and inflammatory cytokines.•The injectable hydrogel could induce the transformation of M1 into M2 in a harsh microenvironment.•Dual mechanism boosts cartilage repair, curbs osteophyte growth in OA joints by optimizing microenvironment.