AbstractAlzheimer's disease (AD) is one of the most common neurodegenerative diseases in the elderly population. Despite significant advances in studies of the pathobiology on AD, there is still no effective treatment. Here, an erythrocyte membrane‐camouflaged nanodrug delivery system (TR‐ZRA) modified with transferrin receptor aptamers that can be targeted across the blood–brain barrier to ameliorate AD immune environment is established. Based on metal‐organic framework (Zn‐CA), TR‐ZRA is loaded with CD22shRNA plasmid to silence the abnormally high expression molecule CD22 in aging microglia. Most importantly, TR‐ZRA can enhance the ability of microglia to phagocytose Aβand alleviate complement activation, which can promote neuronal activity and decrease inflammation level in the AD brain. Moreover, TR‐ZRA is also loaded with Aβaptamers, which allow rapid and low‐cost monitoring of Aβplaques in vitro. After treatment with TR‐ZRA, learning, and memory abilities are enhanced in AD mice. In conclusion, the biomimetic delivery nanosystem TR‐ZRA in this study provides a promising strategy and novel immune targets for AD therapy.