Targeting Endoplasmic Reticulum Stress-ROS-Inflammation Cycle With Antibacterial Heterojunctions for Periodontitis...

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), Ti₃C₂ 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/Ti₃C₂ heterojunction can scavenge ROS and easily transfer electrons from H₂O₂ 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.