An “anaerobic invisible” genetically engineered bacterium for periodontitis treatment through temporal modulation on microenvironment

Jiwei Sun; Junshuai Zhang; Haoqi Lei; Qingming Tang; Pingping Ha; Yutian Xia; Ronghua Deng; Yifan Wang; Yunsong Shi; Junyuan Zhang; Yifan Zhang; Zhenshuo Han; Yingjia Huang; Yuzhou Wu; Lili Chen

doi:10.1016/j.dtrs.2025.100002

Dental Research ›› 2026, Vol. 1 ›› Issue (1) :52 -70. DOI: 10.1016/j.dtrs.2025.100002

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An “anaerobic invisible” genetically engineered bacterium for periodontitis treatment through temporal modulation on microenvironment

Jiwei Sun ^a^,^b^,^c^,¹
, Junshuai Zhang ^d^,^e^,^f^,¹
, Haoqi Lei ^a^,^b^,^c^,¹
, Qingming Tang ^a^,^b^,^c
, Pingping Ha ^g^,^h
, Yutian Xia ^a^,^b
, Ronghua Deng ^a^,^b
, Yifan Wang ^a^,^b^,^c
, Yunsong Shi ^a^,^b^,^c
, Junyuan Zhang ^a^,^b^,^c
, Yifan Zhang ^a^,^b^,^c
, Zhenshuo Han ^a^,^b^,^c
, Yingjia Huang ^a^,^b
, Yuzhou Wu ^d^,^e^,^f^,^*
, Lili Chen ^a^,^b^,^c^,^**

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^a Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China

^b School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030, China

^c Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration , Wuhan 430022, China

^d Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology , Wuhan 430074, China

^e Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology , Wuhan 430074, China

^f State Key Laboratory of Materials Processing and Die & Mould Technology, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology , Wuhan 430074, China

^g Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), School of Dentistry, The University of Queensland , Brisbane, Qld, Australia

^h The University of Queensland, School of Dentistry , Brisbane, Qld, Australia

^* Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China. E-mail addresses:wuyuzhou@hust.edu.cn (Y. Wu).

^** Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. E-mail addresses: chenlili1030@hust.edu.cn (L. Chen).

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Abstract

Periodontitis is a highly prevalent chronic inflammatory disease, primarily driven by microbial dysbiosis and subsequent dysregulation of host immune responses. Therefore, targeting the pathogenesis, modulating the balance of periodontal microbiota, and subsequently controlling local inflammatory responses may offer an effective therapeutic strategy for periodontitis. Here, we propose a "bacteria-versus-bacteria" temporal therapeutic strategy and developed a genetically engineered strain HbEcN-PEI-MTZ@MnO₂ (HEpM) for periodontitis. This two-stage temporal therapy begins with pH-responsive release of metronidazole (MTZ) anchored on HEpM, eliminating periodontal pathogens and rebalancing the microbial dysbiosis. Concurrently, the engineered HEpM was endowed with a local oxygen supply system via the expression of Vitreoscilla hemoglobin (VHb), which enables HEpM to release oxygen as an oxygen-protective barrier forming a protective "anaerobic invisible cloak" that safeguards HEpM from the self-inflicted cytotoxicity of metronidazole. In the second therapeutic phase, remote thermal activation triggers the expression of anti-inflammatory enzymes to mitigate oxidative stress induced by microbial dysbiosis. Consequently, HEpM temporal therapy effectively reshaped the oral microbial community, reducing periodontal pathogens and biofilm formation. Single-cell RNA sequencing analysis further revealed a reduction in inflammatory CXCL1+ fibroblasts and enhanced fibroblast-centered intercellular communication, which facilitated immune microenvironment remodeling. This study establishes a smart, bacteria-based platform for temporal and targeted therapy of periodontitis, offering a novel paradigm for precision treatment of inflammatory diseases.

Keywords

Engineered bacteria / Temporal therapy / Periodontitis / Microbial remodeling / Periodontal microenvironment

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Jiwei Sun, Junshuai Zhang, Haoqi Lei, Qingming Tang, Pingping Ha, Yutian Xia, Ronghua Deng, Yifan Wang, Yunsong Shi, Junyuan Zhang, Yifan Zhang, Zhenshuo Han, Yingjia Huang, Yuzhou Wu, Lili Chen. An “anaerobic invisible” genetically engineered bacterium for periodontitis treatment through temporal modulation on microenvironment. Dental Research, 2026, 1 (1) : 52-70 DOI:10.1016/j.dtrs.2025.100002

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