Engineered Poly(ethylene glycol)‐Alendronate‐Magnesium Hydrogels Potentiate Site‐Specific Immunomodulation for the Healing of Osteoporosis Fractures

Abstract Osteoporosis fractures are typically difficult to heal due to excessive and persistent inflammatory activation, hyperactivated osteoclast activity, compromised osteogenic differentiation capacity, and diminished angiogenic potential. Local delivery of therapeutics to promote immunomodulation with enhanced osteogenic differentiation and inhibition of osteoclasts is promising for the repair of osteoporotic fractures. Herein, we report the preparation of poly(ethylene glycol) (PEG)‐alendronate‐magnesium (PAMg) hydrogels by mixing alendronate (ALN)‐conjugated 8‐arm‐PEG‐NHS with magnesium ions (Mg 2+ ) and 8‐arm‐PEG‐NH 2 based on amide formation and metal coordination. The reversible cross‐linking strategy is not only beneficial for the hydrogel formation but also for the release of ALN and Mg 2+ during the hydrogel degradation, which effectively combines the functions of ALN and Mg 2+ . Consequently, the hydrogel can balance osteogenesis and osteoclastogenesis by modulating the immune microenvironment for bone regeneration. Specifically, it effectively promotes the repair of osteoporotic bone defects by inhibiting osteoclast differentiation while simultaneously enhancing osteogenesis and angiogenesis. This study highlights the potential of PAMg hydrogels for treating osteoporosis‐related bone defects, offering new prospects in bone tissue engineering for biomedical applications.