Ligand-dependent activity engineering of Cu-MOFs based on biomimetic strategies for nanozyme-decorated smart hydrogels for therapy of inflammatory bone defects

Reconstructing inflammatory bone defects using stem cell-based therapy faces challenges posed by the oxidative stress microenvironment. Herewith, 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 <i>in vitro</i> 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 has been demonstrated to effectively sustain the viability of stem cells and osteogenic differentiation in environments where there is an elevated level of ROS, and has the potential to promote angiogenesis and modulate the inflammatory microenvironment during the process of rat bone tissue regeneration. It is hypothesised that this smart hydrogel-like material decorated with antioxidant enzymes offers a promising avenue for treating various inflammation-associated disorders, including arthritis, chronic wounds and bone fractures.