Li Shenghong, Fan Zhibo, Zheng Kaijun, Wu Yujie, Zhong Guannan, Xu Xiaomei
Department of Orthodontics, The Affiliated Stomatology Hospital, Luzhou, Sichuan 646000, P.R. China.
Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatology Hospital, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
ACS Biomater Sci Eng. 2025 May 12;11(5):2753-2767. doi: 10.1021/acsbiomaterials.5c00111. Epub 2025 Apr 26.
The overuse of antibiotics has increased the prevalence of drug-resistant bacteria in periodontitis. "Sentinel" gingival fibroblasts, stimulated by pathogenic bacteria, continue to release signaling factors that affect stem cell repair and recruit immune cells, resulting in persistent inflammation in periodontal tissues, eventually leading to the loosening and loss of teeth. Periodontal pathogenic bacteria cause surface hypoxia, and gingival fibroblasts in the inflammatory microenvironment express HIF-1α, promoting hypoxic areas in periodontal pockets. No drug delivery system is available for the hypoxic region of periodontal pockets. We synthesized BI NPs via berberine (BBR) and indocyanine green (ICG) and formed BIP NPs by wrapping BI NPs with polydopamine (PDA), and the BIP NPs were delivered to the hypoxic region of the periodontal pocket by hitchhiking with the anaerobic probiotic (Bif). The BIP NPs released berberin (BBR) under near-infrared (NIR) irradiation, which inhibited the sulfur metabolism of via mild photothermal action and BBR-targeted serine acetyltransferase, resulting in a decrease in resistance to oxidative stress, thus exerting a nonantibiotic bacteriostatic effect. This mild photothermal effect facilitated the uptake of BIP NPs bygingival fibroblasts. Moreover, BBR targeted nuclear factor-erythroid 2-related factor 2 (NRF2) to reduce ferroptosis, and the gingival fibroblast supernatant modulated macrophage polarization through the NF-κB pathway. In the periodontitis rat model, Bif@BIP+NIR treatment carried the drug to deep periodontal pockets, decreasing local gingival ferroptosis and alleviating periodontitis symptoms. To summarize, engineered probiotics target low-oxygen periodontal pockets for drug delivery, for nonantibiotic bacterial inhibition, and gingival fibroblasts to mitigate ferroptosis, thus alleviating periodontitis to reduce periodontitis.
抗生素的过度使用增加了牙周炎中耐药细菌的患病率。受病原菌刺激的“哨兵”牙龈成纤维细胞持续释放影响干细胞修复并募集免疫细胞的信号因子，导致牙周组织持续炎症，最终导致牙齿松动和脱落。牙周病原菌导致表面缺氧，炎症微环境中的牙龈成纤维细胞表达缺氧诱导因子-1α（HIF-1α），促进牙周袋中的缺氧区域形成。目前尚无针对牙周袋缺氧区域的药物递送系统。我们通过黄连素（BBR）和吲哚菁绿（ICG）合成了BI纳米颗粒，并通过用聚多巴胺（PDA）包裹BI纳米颗粒形成BIP纳米颗粒，BIP纳米颗粒通过搭乘厌氧益生菌（双歧杆菌）被递送至牙周袋的缺氧区域。BIP纳米颗粒在近红外（NIR）照射下释放黄连素（BBR），通过温和的光热作用和BBR靶向的丝氨酸乙酰转移酶抑制细菌的硫代谢，导致对氧化应激的抗性降低，从而发挥非抗生素抑菌作用。这种温和的光热效应促进了牙龈成纤维细胞对BIP纳米颗粒的摄取。此外，BBR靶向核因子红细胞2相关因子2（NRF2）以减少铁死亡，牙龈成纤维细胞上清液通过NF-κB途径调节巨噬细胞极化。在牙周炎大鼠模型中，双歧杆菌@BIP+NIR治疗将药物输送到深部牙周袋，减少局部牙龈铁死亡并减轻牙周炎症状。总之，工程益生菌靶向低氧牙周袋进行药物递送，用于非抗生素抑菌，并作用于牙龈成纤维细胞以减轻铁死亡，从而减轻牙周炎。
