Electrochemically derived nanographene oxide activates endothelial tip cells and promotes angiogenesis by binding endogenous lysophosphatidic acid.

Graphene oxide (GO) exhibits good mechanical and physicochemical characteristics and has extensive application prospects in bone tissue engineering. However, its effect on angiogenesis is unclear, and its potential toxic effects are heavily disputed. Herein, we found that nanographene oxide (NGO) synthesized by one-step water electrolytic oxidation is smaller and shows superior biocompatibility. Moreover, NGO significantly enhanced angiogenesis in calvarial bone defect areas in vivo, providing a good microenvironment for bone regeneration. Endothelial tip cell differentiation is an important step in the initiation of angiogenesis. We verified that NGO activates endothelial tip cells by coupling with lysophosphatidic acid (LPA) in serum via strong hydrogen bonding interactions, which has not been reported. In addition, the mechanism by which NGO promotes angiogenesis was systematically studied. NGO-coupled LPA activates LPAR6 and facilitates the formation of migratory tip cells via Hippo/Yes-associated protein (YAP) independent of reactive oxygen species (ROS) stimulation or additional complex modifications. These results provide an effective strategy for the application of electrochemically derived NGO and more insight into NGO-mediated angiogenesis.