Near-infrared-activated CuTA@PDA@PTH nanozymes remodel the osteoarthritic microenvironment for coordinated cartilage protection and subchondral bone repair.

Osteoarthritis (OA) is a progressive whole-joint disorder involving cartilage degeneration, oxidative stress, synovial inflammation, and subchondral bone remodeling. Current treatments mainly provide symptomatic relief and rarely restore joint microenvironmental homeostasis. Here, we developed a multifunctional near-infrared (NIR)-responsive CuTA@PDA@PTH nanozyme, termed CPP, for OA therapy. CPP was constructed through copper-tannic acid coordination, polydopamine coating, and PTH 1-34 incorporation, integrating antioxidant catalytic activity, photothermal responsiveness, and peptide-mediated bioactivity. CPP exhibited uniform morphology, good dispersibility, stable photothermal behavior, and broad-spectrum ROS-scavenging activity with SOD-like and CAT-like functions. In vitro, NIR-activated CPP reduced H₂O₂-induced ROS accumulation, lipid peroxidation, mitochondrial dysfunction, and apoptosis in chondrocytes, while promoting proliferation and restoring cartilage matrix homeostasis. CPP-NIR also downregulated inflammatory and catabolic markers, attenuated M1-associated activation, favored an anti-inflammatory M2-like phenotype, and enhanced BMSC migration and osteogenic differentiation under oxidative stress. In a DMM-induced mouse OA model, intra-articular CPP combined with NIR irradiation prolonged joint retention, attenuated cartilage degeneration, reduced osteophyte formation, improved subchondral bone microarchitecture, and alleviated synovial inflammation. These findings support NIR-activated CPP as a multi-axis nanozyme platform for redox, immune, cartilage, and subchondral bone microenvironment regulation in OA.