Microenvironment‐Heterogeneity‐Driven Self‐Adaptive CuMo Diatomic Nanozyme Hydrogel for NIR‐II Photoacoustic Imaging‐Assisted Periodontitis Theranostics

ABSTRACT Conventional periodontitis management relies on invasive, operator‐dependent diagnostic methods and treatments that do not adapt to the spatially heterogeneous and evolving periodontal microenvironment. To address these limitations, a heterogeneous microenvironment‐responsive theranostic platform (GT/DAzyme) was developed using a CuMo heteronuclear diatomic nanozyme. The platform integrates second near‐infrared (NIR‐II) photoacoustic imaging (PAI) for noninvasive visualization of periodontal pocket depth, which serves as a critical indicator for periodontitis. Atomically dispersed Cu‐N 4 , Mo‐N 4 , and CuMo‐N 6 sites provide pH‐dependent multi‐enzyme‐mimetic activities across heterogeneous periodontal conditions. Within acidic plaque regions, GT/DAzyme exhibited SOD‐POD‐like and GSHOx‐like activities associated with antibacterial effects by superoxide removal, hydroxyl‐radical generation, and glutathione depletion. Under higher‐pH, ROS‐rich gingival crevicular conditions, the system adaptively switches to repair mode via SOD‐CAT‐like activity, which reduced oxidative stress and was associated with improved mitochondrial function. The platform activates the PI3K/Akt pathway for fundamental reprogramming: (i) metabolic reprogramming via GSK‐3β inhibition to correct glycolysis and oxidative phosphorylation. (ii) inhibiting mitochondrial‐dependent apoptotic by regulating the expression of Bcl‐2 and Bax. Together, the integrated PAI‐assisted dynamic therapy establishes a diagnosis‐treatment‐evaluation closed‐loop platform, offering a promising strategy for precise periodontitis management.