首都医科大学

ARTICLE OPEN TLR9-engineered photoresponsive biomimetic nanodecoys for targeted NETs clearance to mitigate periodontitis-associated bone resorption Siyan Liu1, Yitong Liu1, Yingyi Chen1, Yao Jiao2, Rui Zhao1, Yijia Wang1, Jiebing Zhang3, Shuang Zhang4, Yi Liu 1 and Lijia Guo5 Periodontitis is a widespread and multifactorial inflammatory disease, that leads to the progressive destruction of periodontal tissues and resorption of alveolar bone. The treatment of periodontitis is complicated by complex interactions between the host and oral microbiota, as well as difficulties in obtaining satisfactory treatment effects. Although neutrophil extracellular traps (NETs) participate in the process of disease development induced by periodontitis, their persistent accumulation aggravates inflammatory injury and prevents regenerative processes. Therefore, on the basis of the identification of Toll-like receptor 9 (TLR9) as an important receptor for NETs recognition, a biomimetic and photoresponsive nanodecoy system was designed for the enhanced targeting and efficient degradation of NETs. Taking advantage of the inherent DNA-binding property of TLR9 and incorporating DNase I, this nanodecoy system was designed to drive effective NETs clearance. Under near-infrared radiation, the nanodecoys demonstrate photothermal properties to enhance the clearance of NETs and create an environment conducive to bone regeneration. Moreover, this design inhibits osteoclast overactivation and promotes osteoblast-mediated mineralization to modulate the bone remodeling process. These results demonstrate a promising targeted treatment strategy for periodontitis, which includes the targeting and clearance of NETs and inducing bone regeneration. International Journal of Oral Science (2026) 18:57 ; https://doi.org/10.1038/s41368-026-00454-3 INTRODUCTION Periodontitis is a chronic inflammatory disease driven by host‒ microbial interactions, leading to alveolar bone resorption and tooth loss. Neutrophils serve as the first line of defense in the immune system,1 but their prolonged activation and impaired clearance contribute to tissue damage. When plaque microorgan- isms and their products invade periodontal tissues, neutrophils are rapidly recruited to the site and exert their immune effects through multiple mechanisms,2 which help prevent further invasion by pathogens. Neutrophils eliminate pathogens through phagocytosis, releasing large amounts of proinflammatory factors and reactive oxygen species into local tissues via respiratory bursts.3 A key bactericidal mechanism is the formation of neutrophil extracellular traps (NETs), which ensnare pathogens but also exacerbate inflammation if not adequately removed.4 These structures can entrap large numbers of pathogens and kill them efficiently because of the high local concentration of antimicrobial enzymes.5 However, while neutrophils aid in pathogen clearance, the products they release may damage host tissues. In periodontitis, the lifespan of neutrophils is prolonged, and the reduced degradation rate of NETs enhances local inflammation and has more severe consequences.6 NETs degradation relies on extracellular DNases and macro- phage uptake.7 Dysregulated NETs clearance is linked to chronic periodontitis, and restoring degradation capacity after treatment reduces disease severity.8 Therefore, promoting NETs removal holds promise as a therapeutic strategy.9 While exogenous DNase can degrade NETs, its clinical utility is limited by short half-life and lack of targeting.10 Nanomaterial-based systems have been explored to improve NETs clearance, but challenges remain in terms of specificity and efficiency.11–13 Here, we develop a targeted, photoresponsive nanodecoy system for NETs degradation and periodontal tissue repair. The system consists of black phosphorus quantum dots (BPQDs) loaded with DNase I and encapsulated within Toll-like receptor 9 (TLR9)-overexpressing cell membranes. Our research revealed t