The macrophage-derived membrane is widely applied in the targeting nanocarrier for its inflammatory tendency and long circulation ability due to the preservation of membrane protein. Few studies reported the application of macrophage membranes as biotherapeutic agents. To verify the ability of macrophage membrane as a biotherapeutic agent, ischemic stroke was selected as the model disease. Inspired by the features of macrophages infiltrating the ischemic core and the talent of M2 macrophages in modulating the inflammatory microenvironment, an M2 macrophage membrane (M2M)-disguised poly lactic-co-glycolic acid nanoparticles loaded with baicalin (BA) (M2M@BANPs) is developed. The results in vivo and in vitro indicate that M2M@BANPs could efficiently and actively target ischemic brain tissue and accumulate in microglia and neurons due to the coating of M2M. Furthermore, M2M and M2M@BANPs exhibit significant therapeutic effects in salvaging brain tissue damage and neurological functional recovery by reprogramming microglia from M1 to M2, reducing neutrophil infiltration and inhibiting neuronal apoptosis. Together, our fabrication provides a new insight and an applicative perspective for M2M in the therapy of ischemic stroke.