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Lock-equipped six-helix DNA bundle-mediated siSTING delivery ameliorates Alzheimer's disease via cGAS-STING
Manqing Zhang1, Yufei Lan2, Qu Yue1
1Neurosurgery Center, The National Key Clinical Specialty, Engineering Research Center of Diagnostic and Therapeutic Technology and Devices for Cerebrovascular Diseases in Ministry of Education, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, P. R. China.
Abstract:
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.
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