Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood-brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, a novel poly(lactic-co-glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)-responsive phenylborate ester bond exhibiting "do not eat me" signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec-1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half-life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec-1s modulates pathological microglia to a beneficial state, which reduces A beta burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable "do not eat me" CD47 signal remarkably facilitates microglia-targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.