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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:p>Imbalanced production and clearance of amyloid-\u03b2 (A\u03b2) is a hallmark pathological feature of Alzheimer\u2019s disease (AD). While several monoclonal antibodies targeting A\u03b2 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 A\u03b2, 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 A\u03b2, excessive A\u03b2 engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS\u2013STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further A\u03b2 clearance. To address this, we present a nanomedicine approach termed \u201cA\u03b2-STING Synergistic ImmunoSilencing Therapy (ASSIST)\u201d. ASSIST comprises STING inhibitors encapsulated within a blood\u2013brain barrier (BBB)-permeable polymeric micelle that also serves as an A\u03b2 scavenger. Through a multivalent interaction mechanism, ASSIST efficiently destabilizes A\u03b2 plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated A\u03b2 by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive A\u03b2 uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in A\u03b2 clearance. Intravenous administration of ASSIST significantly reduces A\u03b2 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.<\/jats:p>","DOI":"10.1073\/pnas.2427257122","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T11:06:42Z","timestamp":1748430402000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":27,"title":["Nanoimmunomodulation of the A\u03b2-STING feedback machinery in microglia for Alzheimer\u2019s disease treatment"],"prefix":"10.1073","volume":"122","author":[{"given":"Limin","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University","place":["Nanjing, 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