Mimicking Antioxidases and Hyaluronan Synthase: A Zwitterionic Nanozyme for Photothermal Therapy of Osteoarthritis

Abstract Restoring joint homeostasis is crucial for relieving osteoarthritis (OA). Current strategies are limited to unilateral efforts in joint lubrication, inhibition of inflammation, free radicals scavenging, and cartilage regeneration. Herein, by modifying molybdenum disulfide (MoS ₂ ) with Mg ²⁺ ‐doped polydopamine and coating with polysulfobetaines, a dual‐bionic photothermal nanozyme (MPMP) is constructed to mimic antioxidases/hyaluronan synthase for OA therapy. Photothermally enhanced lubrication lowers the coefficient of friction (0.028) in the early stage of OA treatment. The antioxidases‐mimicking properties of MPMP nanozyme contribute to eliminating reactive oxygen and nitrogen species (ROS/RNS) (over 90% of scavenging ratio for H ₂ O ₂ /·OH/O ^· ₂ ^– /DPPH/ABTS ⁺ ) and supplying O ₂ . With NIR irradiation, the MPMP nanozyme triggers thermogenesis (upregulating HSP70 expression) and Mg ²⁺ release, which promotes the chondrogenesis in inflammatory conditions by deactivating NF‐κB/IL‐17 signaling pathways and enhancing MAPK signaling pathway. Benefiting from HSP70 and Mg ²⁺ , MPMP‐NIR shows HAS‐mimicking activity to increase the intracellular (twofold) and extracellular (3.12‐fold) HA production. Therefore, MPMP‐NIR demonstrates superior spatiotemporally therapeutic effect on OA in mice model, in terms of osteophytes (83.41% of reduction), OARSI scores (88.57% of reduction), and ACAN expression (2.70‐fold of increment). Hence, insights into dual‐bionic nanozymes can be a promising strategy for OA therapy or other inflammation‐related diseases.