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While both central microglia and peripheral macrophages are critical for A\u03b2 clearance, their functional impairment in AD inexorably leads to escalating A\u03b2 burden and disease progression. We here report an in situ engineered synthetic A\u03b2 disaggregator (SAD) delivered to macrophages via neuroprotective DHA\u2010based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic A\u03b2 aggregates but also by fundamentally reprogramming peripheral macrophages to enhance A\u03b2 clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral\u2010penetrating SAD both in vitro and in vivo. The SAD can promote cerebral A\u03b2 disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of A\u03b2 and reducing cerebral A\u03b2 accumulation in mouse models. Collectively, these findings uncover a dual\u2010action mechanism of SAD through the synergistic interplay of direct A\u03b2 disaggregation and enhanced macrophage\u2010mediated clearance. In sum, our findings establish that the central\u2010peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA\u2010based in situ fusion protein in AD treatment.<\/jats:p>","DOI":"10.1002\/adma.202520002","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T09:49:38Z","timestamp":1767952178000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthetic Disaggregators Enhance Central\u2010Peripheral Amyloid\u2010\u03b2 Clearance in Alzheimer's Disease"],"prefix":"10.1002","volume":"38","author":[{"given":"Chunwei","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics School of Pharmaceutical Sciences Department of Neurosurgery Jinan 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