DNA-adsorbing nanozyme hydrogel reprograms the immuno-oxidative microenvironment to support stem cell-based cartilage repair in osteoarthritis.

Osteoarthritis (OA) is a prevalent degenerative joint disease, and stem cell therapy is often limited by a hostile joint microenvironment. Excessive reactive oxygen species (ROS) and damage-associated cell-free DNA (cfDNA) cooperatively drive innate immune activation, inflammatory macrophage polarization, and chondrogenic instability, forming an immuno-oxidative barrier to cartilage repair. Here, we developed a bioactive DNA-adsorbing nanozyme hydrogel (MNKB/HA) to remodel this niche and enhance BMSC-mediated cartilage repair. MNKB/HA integrates Mn3O4 nanozymes with Kartogenin (KGN)-engineered bone marrow mesenchymal stem cells (BMSCs) in an injectable hyaluronic acid matrix. Mn3O4 exhibited SOD- and CAT-like activities, scavenging O2·-, H2O2, and ·OH, while efficiently adsorbing cfDNA and CpG-ODN to suppress TLR9/MyD88 signaling and M1 polarization and promote M2 polarization. In vitro, 10 μg/mL Mn3O4 was cytocompatible, protected BMSCs and chondrocytes from H2O2-induced apoptosis, and reshaped inflammatory secretion, with IL-10 increased 8.3-fold and TNF-α, IL-6, and IL-1β reduced. KGN stabilized the chondrogenic phenotype (SOX9, COL Ⅱ, ACAN), while its combination with Mn3O4 synergistically enhanced chondrogenic stability under oxidative/inflammatory stress. In rat OA, intra-articular MNKB/HA reduced OARSI scores, restored COL II and ACAN, decreased MMP13, improved subchondral bone microarchitecture, and attenuated synovitis and osteophytes. MNKB/HA also reduced synovial cfDNA, weakened TLR9 signaling, promoted M2 polarization, and showed intra-articular retention for at least 10 days without notable systemic toxicity. Thus, MNKB/HA remodels the immuno-oxidative niche through synergistic ROS scavenging and cfDNA adsorption, providing a strategy for stem cell-mediated cartilage repair in OA.