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<p>Alzheimer’s disease (AD) pathological progression is intimately linked to microglial inflammatory activation mediated by the cGAS-STING pathway. Small interfering RNA targeting STING (siSTING) is a precise therapeutic to silence STING and interfere with this pathway, but its clinical translation is severely limited by serum nuclease degradation, inadequate blood-brain barrier (BBB) penetration, and suboptimal targeting. We constructed a lock-equipped six-helix DNA bundle for siSTING delivery. Prior to reaching AD lesions, siSTING was efficiently sequestered within the DNA bundle, ensuring its structural integrity; upon arrival at the lesion site, the carrier undergoes a conformational change in response to the high expression of CD64, thereby triggering the controlled release of encapsulated siSTING. Functional assessments showed this system significantly suppressed cGAS-STING activation, reduced cerebral Aβ plaque deposition, and promoted microglial polarization from M1 (proinflammatory) to M2 (anti-inflammatory). These effects ameliorated memory and learning deficits in AD model mice via enhanced neuroprotection, offering a novel platform for precise targeted therapy of AD.</p> Graphical abstract <p></p>

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Lock-equipped six-helix DNA bundle-mediated siSTING delivery ameliorates Alzheimer’s disease via cGAS-STING inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Manqing Zhang,
  • Yufei Lan,
  • Qu Yue,
  • Jinjun He,
  • Lei Li,
  • Huan Zhang,
  • Yaoyuan Dong,
  • Yuankai Wang,
  • Jiankun Lu,
  • Zhijie Lu,
  • Feiyunduo Hao,
  • Sui Chen,
  • Yixiao Jiang,
  • Chao Zhang,
  • Yan Zhao,
  • Hongbo Guo

摘要

Alzheimer’s disease (AD) pathological progression is intimately linked to microglial inflammatory activation mediated by the cGAS-STING pathway. Small interfering RNA targeting STING (siSTING) is a precise therapeutic to silence STING and interfere with this pathway, but its clinical translation is severely limited by serum nuclease degradation, inadequate blood-brain barrier (BBB) penetration, and suboptimal targeting. We constructed a lock-equipped six-helix DNA bundle for siSTING delivery. Prior to reaching AD lesions, siSTING was efficiently sequestered within the DNA bundle, ensuring its structural integrity; upon arrival at the lesion site, the carrier undergoes a conformational change in response to the high expression of CD64, thereby triggering the controlled release of encapsulated siSTING. Functional assessments showed this system significantly suppressed cGAS-STING activation, reduced cerebral Aβ plaque deposition, and promoted microglial polarization from M1 (proinflammatory) to M2 (anti-inflammatory). These effects ameliorated memory and learning deficits in AD model mice via enhanced neuroprotection, offering a novel platform for precise targeted therapy of AD.

Graphical abstract