2D copper nanozyme patches facilitate bone regeneration via interfacial modulation of osteoclast‐osteoblast dynamics

Abstract Bone loss represents a prevalent pathological feature in skeletal disorders, predominantly due to disrupted osteoclast/osteoblast activities at the bone matrix interface. Although interventions utilizing nanozymes to target reactive oxygen species (ROS) represent a promising therapeutic approach, they often suffer from off‐target effects with their focus on the bone microenvironment rather than the cell‐bone interface. Here, we proposed a “bone patching” to‐stop “bone losing” strategy employing a tailored two‐dimensional nanozyme patch (ezPatch) binding to the bone surface. The ezPatch integrates metal‐phenolic network coordination and bone‐binding ligand modification on copper nanosheets. This design confers high affinity for the bone surface, site‐specific ROS scavenging, and oxygen generation via ligand‐metal charge‐transfer‐driven nanozyme activity. In vitro experiments demonstrated that the ezPatch enhanced antioxidant defenses of osteoclasts by upregulating the expression of heme oxygenase 1 and SOD2 and suppressed osteoclastogenesis through inhibition of MAPK signaling and IFN‐β/STAT1/STAT2‐mediated differentiation. In vivo assessments using murine models of osteoporosis and periodontitis revealed that ezPatch significantly attenuated proinflammatory cytokine levels and mitigated bone loss by restoring osteoclast/osteoblast homeostasis. This research introduces a bone‐interface‐targeted nanozyme‐based therapeutic approach for treating bone loss‐related pathologies.