Inflammatory Cytokine Scavenging and Macrophage Metabolism Reprogramming to Orchestrate Inflammatory Bone Regeneration

Abstract

Inflammatory bone defects pose significant challenges due to persistent inflammation and impaired bone regeneration in infectious disorders such as periodontitis and osteomyelitis. Current therapeutic strategies often fail to address immune dysregulation and defective osteogenesis simultaneously. Here, we developed an inflammatory cytokine-scavenging approach using antiinflammatory M2 macrophage membranes to neutralize inflammatory cytokines in the bone healing environment, and selenium-doped bioactive glass nanoparticles (Se-NPs) to reprogram macrophage metabolism, thereby creating a favorable environment for inflammatory bone regeneration. The nanospheres were prepared by encapsulating Se-NPs within M2 macrophage membranes (M2@Se-NPs). These nanospheres harness their anti-inflammatory capacity via cytokine receptors to scavenge TNF-α and IL-6, while the sustained release of selenium ions reprograms macrophage metabolism via the NRF2/NF-κB pathway, restoring mitochondrial homeostasis and promoting M2 polarisation. In vitro, M2@Se-NPs effectively attenuated macrophage inflammation and inhibited NF-κB activation. Conditioned medium from M2@Se-NPs-treated macrophages further enhanced the osteogenic differentiation of bone marrow stromal cells and promoted angiogenesis of human umbilical vein endothelial cells. In a murine inflammatory cranial defect model, M2@Se-NPs not only mitigated local inflammation by downregulating TNF-α and upregulating ARG-1, but also significantly enhanced osteogenic differentiation and bone matrix formation. This study demonstrates the triple therapeutic roles of M2@Se-NPs in immune modulation, angiogenesis, and bone repair, presenting a novel biomimetic solution for inflammatory bone regeneration.