Effective bone regeneration requires the integration of immune and mechanical signals, which current biomaterials often fail to achieve. To address this, an immunomodulatory scaffold is developed combining 3D printing and electrospinning, designed to mimic the bone and periosteum. The scaffold features an outer electrospun nanofiber mat and an inner 3D-printed core, creating a biomimetic structure that facilitates the polarization of macrophages into pro-inflammatory (M1) and anti-inflammatory (M2) states under physiological fluid shear stress (FSS). RNA sequencing revealed the pivotal role of ion channels, particularly potassium channels, in the dynamic polarization of macrophages. The scaffold also supports mesenchymal stem cell-driven osteogenesis, establishing a synergistic environment for bone repair. This dual-function scaffold holds promise for enhancing tissue regeneration, especially in immune-compromised conditions, by integrating mechanotransduction and immune modulation within a single platform. Our findings provide a novel approach to overcoming the limitations of existing biomaterials and expanding their applications in regenerative medicine.