A ROS-Responsive Coordination Nanoplatform Integrates Antibacterial Activity with STING-Activating Immunomodulation...

Antibacterial treatment reduces residual bacterial burden in periodontitis, but rapid bacterial killing and lysis can also increase exposure to danger signals such as bacterial DNA (bDNA), which can contribute to cGAS-STING-associated innate immune activation. To address this bactericidal stress-associated inflammation, we constructed a ROS-responsive coordination nanosystem, CPLEA, in which the STING inhibitor C-176 was incorporated during Ag⁺-mediated co-assembly of epicatechin and the sulfur-containing PEG ligand methoxy poly(ethylene glycol)-dihydrolipoic acid (mPEG-DHLA), thereby integrating antibacterial activity with the regulation of post-bactericidal STING-associated inflammation. Without compromising bacterial killing, CPLEA promoted C-176 release under oxidative conditions, and the release profile showed temporal overlap with bacterial killing and bDNA exposure. CPLEA attenuated the inflammatory state of macrophages and relieved the suppression of hPDLSC osteogenic differentiation by macrophage-conditioned medium. Transcriptomic analysis indicated downregulation of cytosolic DNA sensing, NF-κB, IL-17, and osteoclast differentiation programs. In a ligature-induced mouse model of periodontitis, CPLEA attenuated local inflammation and TRAP-positive osteoclast accumulation and reduced alveolar bone loss. Collectively, these findings support bactericidal stress-associated STING signaling as a relevant target during local antibacterial treatment of periodontitis and position CPLEA as a feasible materials-based approach for this purpose. STATEMENT OF SIGNIFICANCE: Periodontitis treatment often requires additional antimicrobial control after mechanical debridement, yet rapid bacterial killing and lysis can increase the exposure of bacteria-derived danger signals and thereby sustain host inflammatory responses. This study develops an oxidation-responsive coordination nanoplatform that integrates antibacterial activity with STING-targeted immunomodulation. By incorporating the STING inhibitor C-176 into an Ag⁺-mediated coordination system, CPLEA enables oxidation-promoted C-176 release within a temporal window overlapping bacterial killing and bacterial DNA exposure. The study further demonstrates that early C-176 intervention more effectively regulates STING-associated inflammatory signaling than delayed intervention. CPLEA attenuated macrophage inflammatory responses, alleviated inflammation-associated suppression of periodontal ligament stem cell osteogenic differentiation, and reduced inflammation, osteoclast accumulation, and alveolar bone loss in experimental periodontitis. These findings highlight the importance of immunomodulator availability during the early phase of bactericidal treatment and provide a biomaterials strategy for integrating residual bacterial control with local host modulation.