TLR9-engineered photoresponsive biomimetic nanodecoys for targeted NETs clearance to mitigate periodontitis-associated bone resorption

Abstract

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.

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Funding

Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)(L2510006)

National Natural Science Foundation of China (National Science Foundation of China)(82470936)

Beijing Municipal Administration of Hospitals Incubating Program (PX2023054)

Beijing Physician Scientist Training Project (BJPSTP-2025-29), the Basic-Clinical Joint Research and Cultivation Platform of Capital Medical University (JLPYPT2025012), the Innovation Foundation of Beijing Stomatological Hospital, Capital Medical University (CXJJ25101),the Beijing Municipal Administration of Hospitals’ Youth Programme (QML20231506).

Capital's Funds for Health Improvement and Research (2024-1-2141)

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