Neutrophil extracellular traps (NETs) are highly associated with inflammatory response and vascular injury after ischemic stroke. As the primary degrader of NETs, DNase 1 is limited by easy deactivation and low efficiency of crossing the blood-brain barrier (BBB). Here, we develop a M2 macrophage-derived exosomal (M2exo) system for DNase 1 delivery to achieve enhanced ischemic stroke therapy. The nanoplatform can cross the BBB through transcytosis of exosomes, subsequently clearing NETs by DNase 1 to inhibit inflammatory factors release and prevent vascular injury. Moreover, M2exo induced the polarization of M1 microglia to M2 phenotype, alleviating neuroinflammation via producing anti-inflammatory cytokines. This nanoplatform exhibits significant efficiency of reducing brain infarct area, improving long-term neurologic outcome, and promoting BBB remodeling. The mechanism for the synergistic effect from M2exo and DNase 1 is unveiled at the genetic level through transcriptome analysis. This work provides a paradigm of improving the effectiveness of ischemic stroke therapy.