Bioinspired cascade nanozymes reprogram osteoarthritic joints: Mn-Nb ₂ C-CeO ₂ 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 IL-1β and TNF-α; 4) Cartilage regeneration via pH/ROS-responsive simvastatin(SIM) release and nanocatalysis, upregulating SOX9 and Col2a1 while inhibiting MMP-13 and 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.