Targeting Endoplasmic Reticulum Stress‐ROS‐Inflammation Cycle With Antibacterial Heterojunctions for Periodontitis Therapy

In periodontitis, recalcitrant biofilms and the vicious endoplasmic reticulum (ER) stress‐ROS‐inflammation cycle cause persistent inflammatory osteolysis. However, current treatments mainly alleviate infection and inflammation, without targeting this ER stress‐centered etiological circuit. Herein, we report the de novo design of an ER‐regulating heterojunction (ERR‐HJ), composed of cobalt selenide (CoSe), Ti 3 C 2 MXene, and taurine, for periodontitis treatment via bacterial clearance, ER homeostasis maintenance, and alveolar bone regeneration. Our studies demonstrate that the unique structure of the CoSe/Ti 3 C 2 heterojunction can scavenge ROS and easily transfer electrons from H 2 O 2 to bacterial membranes, which disrupts bacterial respiration and metabolism. At the cellular level, the heterojunction with taurine activates selenoprotein metabolism, restores redox balance, and alleviates ER stress by dampening the PERK‐CHOP pathway, collectively reprogramming macrophages towards a tissue‐regenerative M2 phenotype while inhibiting their osteoclastogenic differentiation. Strikingly, the osteogenic differentiation of human periodontal ligament cells is profoundly boosted. In periodontitis models, the ERR‐HJ promotes tissue repair and reduces alveolar bone resorption through concomitant suppression of oxidative stress, ER stress, and inflammation, suggesting the disruption of the self‐perpetuating cycle. This work furnishes an intriguing avenue for developing innovative heterojunction biomaterials to treat bacterial infection‐associated disorders by integrating bacterial killing and ER stress‐ROS‐inflammation cycle inhibition.