Bioinspired cascade nanozymes reprogram osteoarthritic joints: Mn-Nb₂C-CeO₂ mediated immuno-redox circuitry for self-healing cartilage

Osteoarthritis (OA), a debilitating joint disorder affecting millions worldwide, is characterized by persistent inflammation, oxidative stress, and irreversible cartilage breakdown, yet remains without disease-modifying therapies. Inspired by natural enzymatic cascades, we developed a bioinspired nanocomposite hydrogel, N,S-doped Mn-Nb (C-CeO), that mimics endogenous antioxidant pathways to reprogram the OA microenvironment. This system combines N,S-doped Mn-Nb₂C MXene nanosheets with CeO₂ nanozymes within a boronate ester-crosslinked hydrogel, forming an “immuno-redox circuitry” with four synergistic functions: (1) cascade reactive oxygen species (ROS) scavenging via superoxide dismutase-like Mn-Nb₂C and catalase-like CeO₂, amplified by photothermal enhancement under near-infrared irradiation; (2) broad reactive nitrogen species clearance, removing peroxynitrite (ONOO⁻), nitric oxide (NO), and nitroxyl (NO⁻) to mitigate inflammation; (3) immunomodulation through Mn²⁺-activated cGAS-STING signaling, which promoted macrophage polarization toward the M2 phenotype, concomitantly reducing the levels of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α); (4) cartilage regeneration via pH/ROS-responsive simvastatin (SIM) release and nanocatalysis, upregulating SRY-box transcription factor 9 (SOX9) and Col2a1 while inhibiting matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). In a murine OA model, the system reduced synovitis by 60%, restored 80% of cartilage thickness, and suppressed osteophyte formation, outperforming single-component treatments. This strategy pioneers a “self-healing cartilage” approach by integrating nanocatalysis with immunoengineering for transformative OA therapy.