Bone Morphogenetic Protein-2–Derived Peptide-Conjugated Nanozyme-Integrated Photoenhanced Hybrid Hydrogel for Cascade-Regulated Bone Regeneration

Critical-sized bone defects present a clinical challenge due to their limited self-repair capacity. Application of bone tissue-engineering scaffolds often overlooks the dynamic modulation of the microenvironment, resulting in unsatisfactory bone-regeneration outcomes. In this study, a bone morphogenetic protein-2-derived peptide-loaded honeycomb manganese dioxide (BHM) nanozyme was incorporated into a composite hydrogel (BHM@CG) composed of l-arginine-modified methacrylated carboxymethyl chitosan and gallic acid-grafted methacrylated gelatin. This hydrogel demonstrated a cascade-regulated enhancement of hemostasis, antibacterial activity, anti-inflammatory effects, and osteogenesis. Initially, the BHM@CG hydrogel achieved rapid hemostasis by quickly adhering to irregular defects upon injury. Subsequently, it displayed robust antibacterial activity through synergistic hydrogen bonding, hydrophobic interactions, and cationic interactions. Meanwhile, the BHM nanozyme and polyphenol groups from gallic acid effectively eliminated reactive oxygen species, enabling long-term inflammation regulation. Finally, sustained release of bioactive components promoted cell migration, angiogenesis, and osteogenesis, achieving a bone-formation rate of nearly 40% in a critical-sized calvarial defect model by week 8. More interestingly, the hydrogel also demonstrated efficient antibacterial and bone-regeneration capabilities in an infected critical-sized calvarial defect model. Overall, this hydrogel dynamically modulated the bone-defect microenvironment and effectively enhanced bone regeneration, offering a promising strategy for critical-sized bone-defect repair.