Reconstructing the ischemic osteogenic microenvironment through hierarchical scaffolds orchestrating Mg(2+) signaling and neuropilin-1-mediated angiogenesis.

Ischemic bone defects remain a major challenge in bone tissue engineering, primarily due to insufficient angiogenesis caused by severely compromised local blood supply. Here, we develop a bioactive implant that mechanistically amplifies magnesium-induced angiogenesis by integrating pro-angiogenic liposomes encapsulating neuropilin-1 (NRP-1) with a 3D-printed magnesium (Mg) alloy porous scaffold. The customized Mg scaffold matched defect morphology, provided reliable mechanical support, and featured interconnected micropores to facilitate bone ingrowth and integration. Composite surface coatings simultaneously moderated the rapid degradation of Mg and supplied abundant binding sites for NRP-1-loaded lipos, enabling coordinated regulation of angiogenesis and osteogenesis. In an ischemic bone defect model, the scaffold significantly enhanced neovascularization, bone formation density, and interfacial osseointegration. Mechanistically, the controlled release of Mg(2+) promoted osteogenic differentiation and upregulated Vascular Endothelial Growth Factor A (VEGFA) expression, establishing a biochemical foundation for angiogenesis. Importantly, the incorporation of NRP-1 further potentiated VEGFA-VEGFR2 signaling, markedly amplifying angiogenic efficacy. Collectively, this work identifies an Mg/NRP-1-mediated coupling axis of osteogenesis and angiogenesis, providing a mechanistically informed strategy for bone regeneration in severely ischemic microenvironments.