Nano-immunomodulation of the Aß-STING feedback machinery in microglia for Alzheimer's disease treatment

Imbalanced production and clearance of amyloid-ß (Aß) is a hallmark pathological feature of Alzheimer's disease (AD). While several monoclonal antibodies targeting Aß 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 Aß, 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 Aß, excessive Aß 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 Aß clearance. To address this, we present a nanomedicine approach termed “Aß-STING Synergistic ImmunoSilencing Therapy (ASSIST)”. ASSIST comprises STING inhibitors encapsulated within a blood-brain barrier (BBB)-permeable polymeric micelle that also serves as an Aß scavenger. Through a multivalent mechanism, ASSIST efficiently destabilizes Aß plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated Aß by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive Aß uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in Aß clearance. Intravenous administration of ASSIST significantly reduces Aß 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. Overall design: A is the control, the administration is Saline, Z is the administration group, the administration of ASSIST, H is the administration group, the administration of H151-NP, and the mice in the above three groups are all 5xFAD mice