Functionalized Metal‐Organic Frameworks Loaded with Ultra‐Small Pt‐Se Nanoenzymes Promote Osteoarthritis Repair via Efficient ROS Scavenging and Macrophage Polarization Modulation

Oxidative stress, hypoxia, and chronic inflammation are key factors driving the progression of osteoarthritis (OA). Nanozymes, which exhibit catalytic activity similar to natural enzymes, is able to promote OA repair through antioxidant, hypoxia alleviation, and regulation of the inflammatory microenvironment, demonstrating significant application potential in OA treatment. In this study, ultra-small binary hybridized Se-doped Pt nanoparticles (PS NPs) are loaded into Zr-based metal-organic frameworks (MOFs) and further encapsulated with oxidized chondroitin sulfate (OCS), ultimately yielding a novel nano-platform (OCS@MOF@PS) for effective OA repair. Due to the bimetallic synergistic catalytic effect, PS NPs exhibited multi-enzyme mimetic activities. In vitro and in vivo studies have demonstrated that OCS@MOF@PS effectively scavenged intracellular ROS, alleviated hypoxia in macrophages, and induced their polarization toward the M2 phenotype. This effect may be associated with the regulation of the PI3K/Akt/mTOR signaling pathway. In OA rat model, OCS@MOF@PS significantly attenuated OA joint damage, achieving 78.25 ± 0.28% and 75.70 ± 0.55% reductions in international cartilage repair society (ICRS) score and Mankin score, respectively, at day 56 post-treatment. In conclusion, this nano-platform, with efficient ROS scavenging activity, hypoxia-alleviating capability and excellent biocompatibility, represents a promising therapeutic strategy for OA and other inflammatory diseases fueled by oxidative stress.