Zeman Qin, Jiaqian You, Qianyi Wu, Abudusaimi Maimaiti, J. Li, Qinmei Wang, Wei Teng
ABSTRACT Periodontitis, the sixth most significant global pandemic driven by bacterial biofilms, is characterized by cytotoxic reactive oxygen species (ROS) and histolytic matrix metalloproteinases (MMPs) accumulation, resulting in progressive periodontal destruction. Current therapies are limited by diagnostic inaccuracy, incomplete biofilm elimination, and inadequate tissue regeneration. To address these challenges, an injectable theranostic Ce6@PEG‐MoO x ‐loaded hydrogel through facile construction is proposed, encompassing an intelligent closed‐loop for comprehensive periodontitis management. After being injected into periodontal pockets, the hydrogel adheres to tissues and responds to microenvironmental MMPs, realizing on‐demand therapeutic release. By integrating photoacoustic imaging, the hydrogel facilitates noninvasive, precise and reproducible measurement of porcine periodontal pocket depths, enabling periodontitis diagnosis and monitoring. Subsequently, released oxygen‐vacancy‐rich MoO x nanozyme mitigates cellular oxidative stress, generates O 2 to enhance Ce6‐mediated photodynamic eradication of deep‐seated biofilms, and scavenges residual ROS after bactericidal process. Notably, this system avoids off‐target ROS generation and photothermal damage, preserving surrounding tissues including dental pulp, thus exhibiting exceptional light‐controlled ROS‐modulation. Furthermore, released Mo activates the PI3K/AKT pathway to upregulate angiogenic factors, reprograms M2 macrophages polarization, and stimulates osteogenesis of periodontal stem cells. Altogether, this self‐adaptive ecosystem integrates diagnosis, monitoring, biofilm debridement, and tissue regeneration, establishing a closed‐loop precision therapy for periodontitis with significant clinical potential.