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Ultrasound‐Activated Nanoprobiotic Hydrogel Disrupts the Oral‐Brain Axis to Alleviate Diabetic Periodontitis and Cognitive Decline

Lu Yang,Yazhen Li,Manman Xu,Yongjie Luo,Chengxinyue Ye,Jie Zhou,Jun Wang,Xiaoxia Jiang,Xiong Lu,Chaoming Xie

Published 2025 in Advanced Functional Materials

ABSTRACT

Diabetes‐associated periodontitis and cognitive dysfunction form a vicious cycle that impairs tissue repair. Polyphenol‐engineered artificial nanoprobiotics using ultrasound‐responsive dihydrocaffeic acid (DA)‐mediated Fe/Zn bimetallic porphyrin MOFs (Fe‐TCPP‐DA‐Zn), integrated into adaptive hydrogels, is developed. This design enables microenvironment‐responsive antibacterial action through enhanced sonodynamic performance via bandgap reduction, while DA simultaneously restores oral microbiota balance. Zinc ions coordinate dual‐function bone regulation by inhibiting osteoclasts and activating osteoblasts. Single‐cell analysis reveals macrophage‐fibroblast crosstalk as the regeneration driver in diabetic periodontitis. The hydrogel system demonstrates bidirectional therapeutic effects, promoting periodontal soft/hard tissue reconstruction while alleviating anxiety‐like behaviors through oral‐brain axis modulation. The findings propose an antioxidant nanoprobiotic strategy to break the oral‐systemic disease cycle, providing new insights into microbiome‐brain interactions.

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