A Redox‐Active Manganese Nanocluster Reverses Depression‐Impaired Bone Regeneration via Targeting Cellular Senescence, Lymphangiogenesis, and the Muscle–Bone Metabolic Axis

Depression, a prevalent chronic psychological disorder in aging populations, is increasingly recognized for its deleterious impact on bone regeneration; yet its pathological mechanisms and targeted therapies remain underexplored. Here, a rationally engineered tetranuclear manganese nanocluster (Mn₄), supported by a heptadentate chelating ligand (TPDP), as a multifunctional nanozyme platform to combat depression-induced skeletal dysfunction, is introduced. Utilizing a murine chronic restraint stress model combined with tibial drill-hole injury, it is demonstrated that depression impairs bone healing through a complex interplay of cellular senescence, inflammatory dysregulation, compromised lymphatic vessel proliferation, and disruption of the muscle-bone metabolic axis. Notably, conventional neurogenic activation via β₂-adrenergic signaling fails to restore bone regeneration under depressive conditions, highlighting the unique and multifactorial nature of psychosocially mediated skeletal injury. Mn₄ treatment significantly attenuates stromal cell senescence, reduces inflammatory gene expression, promotes intraosseous lymphangiogenesis, and improves skeletal muscle atrophy, collectively restoring bone repair capacity. Mechanistically, these effects are attributed to the nanocluster's cooperative redox activity, multivalent manganese centers, and tunable catalytic behavior. These findings provide a new therapeutic paradigm integrating redox nanomedicine with bone-muscle-immune crosstalk, offering translational promise for age-related and mood disorder-associated skeletal diseases.