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Published on: July 21, 2023
A mitochondria-targeted nanoantioxidant restores alveolar bone homeostasis in periodontitis by quenching ROS and
Ning Huang1, Lingyan Cao1, Yue Xu2
1Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, 639 Zhizaoju Road, Shanghai, 200011, China.
Abstract:
Prolonged periodontal inflammation and progressive alveolar bone loss are typical manifestations of periodontitis. Antioxidative therapies targeting the central role of reactive oxygen species (ROS) have been explored, but lack of subcellular specificity limits efficacy. Mitochondria function as an upstream redox hub that drives oxidative stress, inflammatory responses, and alveolar bone resorption, making mitochondrial redox modulation a promising yet underexplored strategy for periodontitis therapy. Herein, we developed a mitochondria-targeted, redox-responsive nanocomposite (TC/pSeSe) that enables programmable redox modulation of the pathological periodontal microenvironment. The antioxidative core consists of a ROS-responsive diselenide-containing copolymer (pSeSe) capable of selenium release, while the triphenylphosphine/chitosan (TC) coating confers mitochondrial-targeted, controlled redox activity, mucosal retention and cationic antibacterial properties. With preferential mitochondrial localization, TC/pSeSe undergoes diselenide bond cleavage and selenium release under oxidative stress, thereby restoring mitochondrial redox homeostasis and attenuating downstream mitochondrial DNA (mtDNA)-cGAS-STING-mediated inflammatory signaling. Through combined ROS scavenging and selenium-mediated support, TC/pSeSe mitigates ferroptosis in a partially glutathione peroxidase 4 (GPX4)-dependent manner and restores osteogenic potential in bone marrow-derived stem cells. In parallel, TC/pSeSe exhibits antibacterial activity against periodontal pathogens through combined selenium and the cationic TC coating functionalities. In vivo, TC/pSeSe restored alveolar bone regeneration and attenuated periodontal inflammation. Collectively, this study proposes a mitochondria-centered redox modulation strategy, providing a comprehensive and promising therapeutic approach for periodontitis treatment.
Insights
This study introduces a novel nanocomposite targeting mitochondria to treat periodontitis. The therapy modulates redox balance, reduces inflammation, and promotes bone regeneration by delivering selenium specifically to damaged cells.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Periodontal Medicine
Background:
- Periodontitis involves chronic inflammation and alveolar bone loss, driven by oxidative stress.
- Current antioxidative therapies lack subcellular specificity, limiting their effectiveness.
- Mitochondria are key regulators of oxidative stress and inflammation in periodontitis.
Purpose of the Study:
- To develop a mitochondria-targeted, redox-responsive nanocomposite for periodontitis treatment.
- To investigate the therapeutic potential of modulating mitochondrial redox homeostasis.
- To evaluate the efficacy of the nanocomposite in restoring periodontal health.
Main Methods:
- Development of a diselenide-containing copolymer (pSeSe) and triphenylphosphine/chitosan (TC) coating for mitochondrial targeting.
- In vitro assessment of nanocomposite localization, redox modulation, and effects on stem cells and periodontal pathogens.
- In vivo evaluation of alveolar bone regeneration and anti-inflammatory effects in a periodontitis model.
Main Results:
- The TC/pSeSe nanocomposite selectively targets mitochondria and releases selenium under oxidative stress.
- It restores mitochondrial redox homeostasis, attenuates inflammation via the mtDNA-cGAS-STING pathway, and mitigates ferroptosis.
- The nanocomposite promotes osteogenic potential in stem cells, exhibits antibacterial activity, and enhances alveolar bone regeneration in vivo.
Conclusions:
- Mitochondria-centered redox modulation is a promising therapeutic strategy for periodontitis.
- The developed TC/pSeSe nanocomposite offers a comprehensive approach by scavenging reactive oxygen species (ROS) and delivering selenium.
- This approach effectively treats periodontitis by addressing inflammation, bone loss, and bacterial infection.
