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Here, we report a synthetic efferocytic receptor (SER) integrating A\u03b2-targeting scFv, efferocytosis receptor backbone based on TIM4 and downstream signal for microglia (MG) reprogramming, which enabled selective elimination of A\u03b2 without inducing an inflammatory response. Specifically, our in-house\u2013customized MG-editing mRNA lipid nanoparticles (MERLINs) efficiently introduced SER mRNA into MG to generate A\u03b2-specific SER-MG in situ. SER-MG exhibited robust A\u03b2-specific phagocytosis and stimulated anti-inflammatory efferocytosis typical signaling in vitro. In a mouse model of AD, SER expression in the MG markedly increased the clearance of A\u03b2 and dampened inflammation, resulting in improved behavioral outcomes along with substantially reduced synapse elimination. Our findings establish that AD-associated aberrant MG can be in situ reprogrammed with SER for A\u03b2 clearance in an anti-inflammatory manner, with broad application in other inflammation-related diseases.<\/jats:p>","DOI":"10.1126\/sciadv.ads6613","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T17:58:57Z","timestamp":1752083937000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":12,"title":["Synthetic efferocytic receptor microglia enhances anti-inflammatory clearance of amyloid-\u03b2 for AD treatment in mice"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3118-5740","authenticated-orcid":true,"given":"Lijuan","family":"Shao","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 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