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

ABSTRACT 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 FPEG 5 , which exhibits dual functionality as a potent reactive oxygen species (ROS) scavenger and an immunomodulator. Beyond its antioxidant activity, FPEG 5 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, FPEG 5 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.