Mechanism-Driven Nanoformulations for Cognitive Impairment Induced by Intermittent Hypoxia and Periodontitis

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&mSiO₂-TPP-VB Janus nanoformulation is developed for hierarchical neuron-to-mitochondria targeting. The inherent asymmetry of the Au&mSiO₂ 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.