Diatomic Mn/Ca Nanozymes with Jaw Vascular Unit Mimicry for Triple‐Enzyme Synergistic Therapy of Osteoradionecrosis

Osteoradionecrosis of the jaw (ORNJ) causes debilitating complications, while current therapies risk tissue damage and vascular insufficiency. Herein, jaw vascular unit (JVU)-biomimetic nanozymes are developed by coating Mn/Ca diatomic sites nanozymes (Mn-CaDSN) with hybrid membranes (HM) from M2 macrophages and osteogenically induced human bone marrow mesenchymal stem cells (HBMSCs). Mn-CaDSN exhibited synergistic superoxide dismutase-like, catalase-like, and glutathione peroxidase (GPx)-like activities, and the maximized GPx-like catalytic activity of Mn-CaDSN (V_max = 0.69 mm·min^-1) is 2.1-fold higher than Mn single-atom controls (V_max = 0.33 mm·min^-1). Density functional theory calculations revealed that Ca sites optimized substrate adsorption and O─H bond cleavage via d-band center modulation. HM coating enabled targeted JVU delivery, enhancing cellular uptake and reprogramming irradiated macrophages toward M2 polarization (ARG-1⁺ cells increasing 3.8-fold) and osteogenic differentiation (ALP area uprising 4.2-fold). In irradiated cells, the nanozymes concurrently eliminated reactive oxygen/nitrogen species (RONS), activates mitophagy (mitochondrial-lysosomal colocalization colocalization uprising 50%), and suppresses cuproptosis (HSP70 decreasing 45%; intracellular Cu²⁺ decreasing 30%). Loaded Dl-3-n-butylphthalide (NBP) further enhanced angiogenesis in vivo. In rat ORNJ models, NBP@Mn-CaDSN@HM promoted mucosal healing and increased bone volume fraction (BV/TV increasing 2.3-fold vs irradiated controls) by rebalancing immune-vascular-osteogenic microenvironments. This work establishes a paradigm of JVU biomimetics integrated with diatomic nanozymes for comprehensive ORNJ therapy.