Self-Regulated ROS Nanoplatform Enables Sequential Antibacterial Therapy and Inflammation Resolution in Periodontitis

Infection-associated inflammatory diseases such as periodontitis are driven not only by persistent bacterial biofilms but also by dysregulated host immune responses amplified by excessive reactive oxygen species (ROS). Although antimicrobial photodynamic therapy (PDT) efficiently eradicates pathogens, uncontrolled ROS accumulation often aggravates inflammation and impairs tissue repair, limiting its clinical translation. Here, we report a self-regulated ROS nanoplatform based on a one-dimensional porphyrin–diketopyrrolopyrrole covalent organic framework (COF) loaded with the natural flavonoid naringin (COF-Por-DPP@Naringin), which enables temporally programmed ROS generation and scavenging. Under 660 nm irradiation, the COF scaffold induces a transient ROS surge sufficient to eradicate Porphyromonas gingivalis and Fusobacterium nucleatum biofilms with 99.43 ± 0.56% and 99.87 ± 0.22% killing efficiency, respectively. Subsequently, the controlled release of naringin selectively scavenges residual ROS, suppresses pro-inflammatory cytokine expression, and alleviates PDT-induced oxidative stress. Transcriptomic analysis of inflammatory macrophages revealed coordinated downregulation of tumor necrosis factor (TNF), interleukin-17 (IL-17), and p53 signaling pathways, indicating ROS-mediated immune-inflammatory reprogramming rather than empirical anti-inflammatory effects alone. In a ligature-induced murine periodontitis model, this sequential ROS regulation effectively reduced bacterial burden, attenuated inflammatory infiltration, preserved alveolar bone architecture, and promoted periodontal tissue repair. Collectively, this work demonstrates that precise temporal regulation of ROS can transform PDT from a purely antimicrobial strategy into an immunomodulatory therapeutic approach, providing a generalizable framework for nanotherapeutic design targeting infection-driven inflammatory diseases.