Mechanism‐Driven Nanoformulations for Cognitive Impairment Induced by Intermittent Hypoxia and Periodontitis
Abstract
ABSTRACT Cognitive impairment is a growing global health challenge, yet its multifactorial drivers remain incompletely understood. Intermittent hypoxia (IH) and periodontitis are identified as significant independent risk factors that frequently co‐occur. This study investigates the mechanisms through which these conditions accelerate cognitive decline. Here, utilizing a comorbid mouse model, we demonstrate that outer membrane vesicles (OMVs) derived from Porphyromonas gingivalis exacerbate IH‐induced mitochondrial oxidative stress and neuroinflammation, leading to neuronal damage and mitochondrial dysfunction in the hippocampus. Specifically, this process is driven by the activation of the HIF‐1α/HMGB1/NLRP3 signaling axis. To target this pathology, an asymmetric RVG‐Au&mSiO 2 ‐TPP‐VB Janus nanoformulation is developed for hierarchical neuron‐to‐mitochondria targeting. The inherent asymmetry of the Au&mSiO 2 Janus architecture enables anisotropic, spatially segregated functionalization of its two distinct domains. The neuron‐targeting RVG peptide and the mitochondria‐targeting ligand TPP are anchored on distinct domains, while vitamin B2 (VB) is encapsulated within the mesopores. Intranasal administration of this nanoformulation achieves precise mitochondrial accumulation in neurons, effectively scavenging reactive oxygen species, suppressing neuroinflammation, and significantly restoring cognitive function. Our findings reveal a molecular pathway through which IH and periodontitis jointly drive cognitive dysfunction and propose a hierarchically targeted nanotherapy for related comorbidities.
Article Details
Authors (16)
Kai‐Run Zhang
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai China
Tianbao Zhu
Department of Chemistry, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers
An‐Qi Liu
Department of Orthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University, School of Medicine. National Clinical Research Center For Oral Diseases Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology Shanghai China
Jia‐Jia Deng
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai China
Ya‐Li Han
Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Shanghai Stomatological Hospital & School of Stomatology Fudan University Shanghai China
Sheng‐Cai Qi
Department of Prothodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai China
Xue Liu
Tian‐Yi Jiang
Department of Neurobiology, School of Basic Medical Science Nanjing Medical University Nanjing China
Ming‐Rui Zhai
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai China
Yu‐Ying He
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai China
Xiu‐Juan Li
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai China
Hong‐Ting Da
Department of Laboratory the First Affiliated Hospital of Anhui Medical University Hefei China
Rui Xu
College & Hospital of Stomatology
Xiaomin Li
Department of Chemistry, Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Molecular Engineering of Polymers, iChem (Collaborative Innovation Center of Chemistry for Energy Materials), Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials
Jun Gao
Qingdao Institute of Bioenergy and Bioprocess Technology
Yue‐Hua Liu
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai China