The "Yin and Yang" of Immunomodulatory Magnesium-Enriched Graphene Oxide Nanoscrolls Decorated Biomimetic Scaffolds in Promoting Bone Regeneration.

Tissue regeneration driven by immunomodulatory agents has emerged as a potential solution for repairing bone defects. However, the therapeutic benefits are compromised by disturbances in the pro- and anti-inflammatory balance. Here, using magnesium nanoparticles (MgNPs) as a template, magnesium-enriched graphene oxide nanoscrolls (MgNPs@GNSs) designed for combinational modulation of the inflammatory response are reported. First, the different effects of graphene oxide (GO) and magnesium ions (Mg2+ ) on Raw264.7 macrophage phenotype transformation are screened. The results reveal that GO activates inflammatory M1 macrophages, and that Mg2+ facilitates repolarization of M1 macrophages to the pro-healing M2 phenotype. With sustained release of Mg2+ , the MgNPs@GNS nanoplatform can orchestrate harmonious type 1 and type 2 inflammatory responses. Mg2+ decrease the internalization of GO and downregulate the nuclear factor kappa-B pathway, which is profoundly involved in the inflammatory process. A series of experiments show that the ordered inflammatory response induced by MgNPs@GNSs stimulates in vitro angiogenesis and osteogenesis through chemotactic, mitogenic, and morphogenic actions. Obvious vascularized bone regeneration is achieved in a rat cranial bone defect model via MgNPs@GNS deposited decellularized bone matrix scaffold. Therefore, the potential of using inherently therapeutic nanomedicine to modulate biomaterial-induced immune responses and thus enhance bone regeneration is demonstrated.