A Smart Bio‐Battery Facilitates Diabetic Bone Defect Repair Via Inducing Macrophage Reprogramming and Synergistically Modulating Bone Remodeling Coupling

Abstract In the diabetic milieu, fluctuations in blood glucose levels, elevated reactive oxygen species (ROS), and abnormal macrophage polarization exacerbate the imbalance of the osteoblast–osteoclast axis, posing significant challenges for the repair of critical‐sized bone defects. Multifunctional conductive biomaterials based on electrical stimulation (ES) therapy present a potential strategy to modulate the adverse inflammatory microenvironment and promote bone regeneration under diabetic conditions. However, traditional complex endogenous implantable battery devices are often bulky and difficult to seamlessly integrate with the body's natural biological processes. Herein, a novel implantable smart bio‐battery—comprising GelMA, tetrafluorophenylboronic acid (FPBA), osteostatin, and graphene oxide (GF‐Os G )—is developed for bone defect regeneration in diabetic inflammatory environments. GF‐Os G bio‐microbatteries can generate microcurrents in high‐glucose environments, reprogramming macrophages to the M2 phenotype and modulating immune responses. A favorable immune microenvironment is a crucial prerequisite for vascular regeneration and bone differentiation. ES can also directly stimulate osteogenic differentiation of bone marrow mesenchymal stem cells and synergistically modulate the osteoblast‐osteoclast axis with Osteostatin to promote bone regeneration. Furthermore, the underlying therapeutic mechanism is elucidated, demonstrating that GF‐Os G promotes osteogenesis via the ERK/P38‐GPX4 axis, effectively enhancing osteogenic differentiation. In vivo experiments revealed that the GF‐Os G can modulate immune responses and facilitate the repair of diabetic bone defects. This innovative approach combines immune regulation with a bio‐microbattery ES system, offering a novel material platform for microcurrent‐enhanced tissue regeneration in diabetic microenvironments.