A Dual-Targeting Strategy Against ROS and GSK-3β With a PEGylated Fullerene/Smart Hydrogel Synergistic System for Diabetic Bone Regeneration.

Diabetic bone regeneration remains a significant clinical challenge due to a hostile microenvironment characterized by oxidative stress and chronic inflammation. Here, we report a structurally defined, pentakis-PEGylated fullerene derivative, termed FPEG5, which exhibits dual functionality as a potent reactive oxygen species (ROS) scavenger and an immunomodulator. Beyond its antioxidant activity, FPEG5 directly targets glycogen synthase kinase-3β (GSK-3β), thereby stabilizing β-catenin and suppressing the Nuclear Factor kappa-B (NF-κB) inflammatory axis. This dual-action mechanism effectively reprograms macrophages from a pro-inflammatory (M1) to a pro-regenerative (M2) phenotype under diabetic conditions. To enable localized therapy, FPEG5 is incorporated into an injectable, glucose- and ROS-responsive hydrogel for on-demand release. This combination effectively reshapes the local immune microenvironment, restores osteogenic differentiation in vitro, and drives robust, bridging bone regeneration in a diabetic calvarial defect model. This work presents a novel therapeutic strategy integrating a target-specific fullerene pharmacophore with a smart delivery system for diabetic osteoregeneration.