Subarachnoid hemorrhage (SAH) often leads to severe early brain injury (EBI) with limited treatment options for alleviating neurological damage. Recent evidence highlights the therapeutic potential of modulating immune pathways in SAH, particularly through targeted regulation of macrophage activity. This study investigates nanobody-engineered outer membrane vesicles (OMVs) as a novel strategy to activate the Fibrinogen-like Protein 2-Stimulator of Interferon Genes (FGL2-STING) pathway, inducing macrophage mitophagy and mitigating EBI. Using genetic engineering, nanobodies targeting FGL2 were fused into OMVs, yielding a stable and functional vehicle that activates mitophagy pathways in macrophages. In vivo, OMV-FGL2 significantly improved cognitive and neurological outcomes in SAH model mice, reducing brain inflammation and apoptosis. Multi-omics analysis revealed that OMV-FGL2 treatment modulates key molecules related to mitophagy and inflammatory pathways, emphasizing its dual functionality in targeted delivery and immune regulation. These findings suggest that nanobody-functionalized OMV-FGL2 represents a promising therapeutic avenue for SAH, enhancing recovery by targeting cellular and molecular pathways critical to inflammation and neural protection.