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

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.