Abstract
Macrophages play pivotal roles at the interface of immune regulation and bone metabolism and frequently exhibit a proinflammatory phenotype that contributes to the osteoporotic microenvironment. We found that dysfunctional macrophages in the osteoporotic niche transferred injured mitochondria to osteoblasts, which was associated with increased cellular senescence and impaired osteogenic function. This detrimental mitochondrial transfer was associated with abnormal accumulation of succinate dehydrogenase (SDH), contributing to maintenance of the proinflammatory phenotype and mitochondrial injury. On the basis of this mechanism, a folate (FA)-modified magnesium-manganese layered double hydroxide (MgMn-LDH) loaded with the SDH inhibitor dimethyl malonate (DMM) was designed to modulate proinflammatory macrophages. This system promoted BNIP3-LC3B-associated mitophagy, which was accompanied by improved mitochondrial quality control, mitochondrial dynamics and mitochondrial transfer capacity. The functional mitochondrial transfer from treated macrophages to neighboring osteoblasts was associated with enhanced osteogenic activity under osteoporotic conditions. Furthermore, MgMn-LDH/DMM@FA treatment significantly ameliorated bone loss and improved bone microarchitecture in ovariectomized mice. Collectively, these findings suggest that mitigating mitochondrial injury and enhancing functional mitochondrial transfer in proinflammatory macrophages may represent a promising strategy for alleviating osteoporosis. An enzyme-active MgMn-LDH-based delivery system provides a potential therapeutic platform for osteoporosis intervention.