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 (Vmax = 0.69 mm·min-1) is 2.1-fold higher than Mn single-atom controls (Vmax = 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.