Lithium‐Doped Hydroxyapatite Nanowires Rejuvenate Senescent Macrophages Via the Lysosome‐Dependent Ferroptosis Axis to Promote Aged Bone Regeneration

Senescent bone repair remains a formidable clinical challenge without an entirely satisfactory strategy. Emerging evidence has identified macrophage senescence as a critical determinant of impaired bone healing in the aged skeleton, and precisely reversing macrophage senescence has therefore emerged as a highly promising therapeutic approach. In this study, guided by multi‐omics features of senescent macrophages, we develop lithium‐doped hydroxyapatite nanowires (Li‐nHAP) and demonstrate that Li‐nHAP effectively alleviates macrophage senescence and subsequently enhances the osteogenic differentiation of aged bone marrow mesenchymal stem cells. Mechanistically, we identify the lysosome‐dependent ferroptosis axis as a previously unrecognized target mediating the anti‐senescent effects of Li‐nHAP in bone marrow‐derived macrophages. Specifically, Li‐nHAP re‐establishes lysosomal homeostasis, including restoring acidity, preserving membrane integrity, maintaining iron storage, and enhancing hydrolytic activity, thereby suppressing ferroptosis and ultimately reversing macrophage senescence. In vivo studies further validate that Li‐nHAP significantly alleviates macrophage ferroptosis and senescence, reduces local iron accumulation, and accelerates bone regeneration in an aged mandibular defect model. Collectively, these findings establish Li‐nHAP as a novel osteo‐immunomodulatory biomaterial that offers a promising strategy for the repair of age‐related bone defects. Li‐nHAP+GelMA promotes mandibular bone regeneration in aged mice by remodeling the senescent immune microenvironment. Local delivery of Li‐nHAP restores lysosomal homeostasis in senescent macrophages, reduces intracellular labile Fe 2 + accumulation, ROS production, and lipid peroxidation, thereby suppressing macrophage ferroptosis and senescence‐associated SASP signaling. This macrophage rejuvenation alleviates the aged inflammatory microenvironment and enhances osteogenesis, ultimately improving bone repair in mandibular defects.