Kartogenin-Loaded Selenium-Prussian Blue Nanogel through ROS scavenging and cartilage regeneration for the mitigation of osteoarthritis.

Osteoarthritis (OA), a degenerative joint disease driven by synovial inflammation, oxidative stress and progressive cartilage degradation, remains a major clinical challenge. While drug-loaded nanozymes offer an effective strategy for OA treatment by scavenging reactive oxygen species (ROS) and delivering therapeutics, their efficacy is limited by insufficient catalytic activity and poor drug retention capacity. Herein, we developed a specific matrix metalloproteinase (MMP) 13-responsive smart nanogel system (M-MA@KSPB) comprising a selenium-doped Prussian blue nanozyme (SPB) core loaded with kartogenin (KGN) and an MMP13-responsive peptide cross-linking hyaluronic acid methacryloyl (HAMA) shell. As MMP13 is a key biomarker of OA progression, the MMP13-triggered responsiveness of M-MA@KSPB enhanced its retention within the joint cavity through targeted structural changes, thereby enabling spatiotemporally precise KGN release for cartilage regeneration. Upon release, the SPB nanozyme exhibited catalase (CAT)-, superoxide dismutase (SOD)-, and glutathione reductase (GR)-like activities, potently scavenging ROS and mitigating oxidative stress. Furthermore, the M-MA@KSPB downregulated pro-inflammatory cytokines (TNF-α, IL-6), while enhancing collagen II synthesis and suppressing MMP13 expression in Lipopolysaccharide (LPS)-stimulated chondrocytes. In a post-traumatic OA rat model, this system inhibited joint inflammation and osteophyte formation, concurrently promoting cartilage regeneration and restoring anabolic/catabolic balance through KGN-mediated repair. This nanogel system offers a new OA treatment strategy by combining anti-oxidative stress therapy with cartilage repair.