Chronic neuroinflammation and accumulation of extracellular amyloid-β (Aβ) plaques are prominent drivers of Alzheimer’s disease (AD) that have been extensively investigated as independent therapeutic targets. We hypothesized that addressing both targets simultaneously could be more effective at treating a complex disease like AD. Here, we introduce a breakthrough strategy that achieves this goal through in vivo engineering of monocytes/macrophages using mRNA-encoded chimeric antigen receptors (CARs). In the 5xFAD mouse model of amyloid-driven AD, systemic delivery of lipid nanoparticles encapsulating mRNAs for Aβ-specific CAR and interleukin-10 (IL-10) was employed to generate CAR-modified monocytes/macrophages (CAR-M). These CAR-Ms efficiently penetrated the blood-brain barrier and mediated Aβ clearance through CAR-directed phagocytosis, while simultaneously attenuating neuroinflammation via localized IL-10 delivery. This dual mechanism strategy protected 5xFAD mice from developing AD pathology and cognitive impairment. Our findings establish the potential of synthetic immunological approaches for treating complex neurodegenerative disease through multifunctional cell reprogramming.