Ligand-Dependent Activity Engineering Cu-MOF Based on Biomimetic Strategies for Nanozyme-Decorated Smart Hydrogel for Therapy of Inflammatory Bone Defects

Reconstructing inflammatory bone defects using stem cell-based therapy faces challenges posed by the oxidative stress microenvironment. Here, inspired by the response mechanism of the intracellular antioxidant defense systems (IADS), we propose MOF nanozymes that mimic the structure of horseshoe crab hemocyanin and find that a ligand engineering strategy can modulate the SOD- and CAT-mimicking activities of MOF-based nanozymes. Through in vitro screening, the most efficient Cu-Imi nanozymes were selected and incorporated into a smart hydrogel (composed of oxidized dextran and dopamine-functionalized gelatin) for inflammatory bone defect treatment. Studies demonstrate that smart hydrogels are able to respond to the acidic microenvironment induced by oxidative stress and early tissue injury by intelligently releasing biomimetic nanozymes, which can effectively eliminate bacteria, alleviate inflammation, and reduce ROS levels. In addition, the smart hydrogel can effectively sustain stem cell viability and osteogenic differentiation in elevated ROS environments, and has the potential to promote angiogenesis and modulate the inflammatory microenvironment during rat bone tissue regeneration. We believe that this smart hydrogel-like material decorated with antioxidant enzymes offers a promising avenue for treat various inflammation-associated disorders, including arthritis, chronic wound and bone fractures.