Multifunctional Nanoparticle Reinforced GelMA Hydrogel for Osteoporotic Pathophysiological Microenvironment Improvement and Bone Defect Regeneration

Abstract Repairing osteoporotic bone defects remains a significant clinical challenge, primarily due to the hostile bone microenvironment characterized by excessive oxidative stress, chronic inflammation, impaired osteogenesis, and compromised angiogenesis. Addressing these pathological conditions through microenvironmental modulation is therefore critical for effective bone regeneration. In this study, a novel photo‐crosslinked hydrogel (GCPM) is developed by integrating polydopamine‐modified cerium oxide nanoparticles (CeO 2 NPs) and magnesium ions (Mg 2 ⁺) into a gelatin methacryloyl (GelMA) matrix. This GCPM hydrogel exhibits excellent physicochemical properties and biocompatibility. With the appropriate release of CeO 2 and magnesium ions, the GCPM hydrogel presents with significant ROS‐scavenging ability, immunomodulatory effects, and angiogenesis. Moreover, in vitro studies further demonstrate the hydrogel's ability to enhance osteogenic differentiation under oxidative stress. Most importantly, in vivo experiments confirm that the GCPM hydrogel significantly accelerates the repair of osteoporotic bone defects. Collectively, this work highlights the therapeutic potential of GCPM hydrogels as a multifunctional biomaterial for treating osteoporotic bone defects by simultaneously remodeling the pathological microenvironment and promoting regeneration.