A novel approach to target and degrade amyloid plaques in Alzheimer's disease (AD) involves genetically engineering macrophages to express a chimeric antigen receptor (CAR) targeting β-amyloid (Aβ). This study demonstrates that CAR-modified macrophages (CAR-Ms) can effectively resorb Aβ plaques in vitro and in vivo. First-generation CAR-Ms had limited persistence and failed to significantly reduce plaque load, prompting the development of next-generation CAR-Ms that secrete M-CSF, enhancing their survival and efficacy. These "reinforced CAR-Ms" significantly reduced plaque load in the hippocampus of aged APP/PS1 mice. The study highlights the potential of CAR-Ms as a platform for targeting and degrading pathogenic material, such as Aβ, in AD. The findings suggest that CAR-Ms could be a promising therapeutic strategy for AD, offering a living drug approach that can respond more dynamically than conventional therapies. The study also addresses the challenges of CAR-M survival and persistence in the brain niche, emphasizing the importance of cytokine secretion for effective in vivo function. While the study shows promising results, further research is needed to improve CAR-M migration and CNS penetration for broader clinical application. The research underscores the potential of CAR-M technology beyond cancer, offering a new approach for AD treatment.A novel approach to target and degrade amyloid plaques in Alzheimer's disease (AD) involves genetically engineering macrophages to express a chimeric antigen receptor (CAR) targeting β-amyloid (Aβ). This study demonstrates that CAR-modified macrophages (CAR-Ms) can effectively resorb Aβ plaques in vitro and in vivo. First-generation CAR-Ms had limited persistence and failed to significantly reduce plaque load, prompting the development of next-generation CAR-Ms that secrete M-CSF, enhancing their survival and efficacy. These "reinforced CAR-Ms" significantly reduced plaque load in the hippocampus of aged APP/PS1 mice. The study highlights the potential of CAR-Ms as a platform for targeting and degrading pathogenic material, such as Aβ, in AD. The findings suggest that CAR-Ms could be a promising therapeutic strategy for AD, offering a living drug approach that can respond more dynamically than conventional therapies. The study also addresses the challenges of CAR-M survival and persistence in the brain niche, emphasizing the importance of cytokine secretion for effective in vivo function. While the study shows promising results, further research is needed to improve CAR-M migration and CNS penetration for broader clinical application. The research underscores the potential of CAR-M technology beyond cancer, offering a new approach for AD treatment.