Nanoimmunomodulation of the Aβ- STING feedback machinery in microglia for Alzheimer's disease treatment

• 成果类型: Article
• 署名作者: Tian, Limin; Long, Guangyu; Zhu, Siqi; Wang, Yuelong; Xu, Pengcheng; Liu, Lifeng; Yao, Hong; Fang, Shentong; Chen, Shuqing; Li, Suxin
• 署名单位: China Pharmaceutical University; Inner Mongolia Medical University; China Pharmaceutical University; China Pharmaceutical University; Huazhong University of Science & Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12453
• DOI: 10.1073/pnas.2427257122
• 发表日期: 2025-06-03
• 关键词: amyloid-beta; activation; neurodegeneration; contributes; progression; deficiency; responses; drives; brain

摘要

Imbalanced production and clearance of amyloid-n (An) is a hallmark pathological feature of Alzheimer's disease (AD). While several monoclonal antibodies targeting An have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and An, as well as their combined influence on AD progression, is poorly understood. Here, we show that while microglia play a protective role in clearing extracellular An, excessive An engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS-STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further An clearance. To address this, we present a nanomedicine approach termed An-STING Synergistic ImmunoSilencing Therapy (ASSIST). ASSIST comprises STING inhibitors encapsulated within a blood-brain barrier (BBB)-permeable polymeric micelle that also serves as an An scavenger. Through a multivalent interaction mechanism, ASSIST efficiently destabilizes An plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated An by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive An uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in An clearance. Intravenous administration of ASSIST significantly reduces An burden and improves cognition in AD mice, with minimal cerebral amyloid angiopathy or microhemorrhages. We provide a proof-of-concept nanoengineering strategy to target the maladaptive immune feedback loop arising from conventional immunotherapy for AD treatment.