An Iron Balance Dual‐Drive Strategy (IBDS) Promotes Bone Regeneration in Smokers by Regulating Mitochondrial Iron Homeostasis

Abstract Cigarette smoke (CS) disrupts mitochondrial iron homeostasis, causing excess free iron to generate reactive oxygen species, leading to oxidative stress and impairing tissue repair. For smokers undergoing bone defect repair, achieving precise control over the balance between mitochondrial free iron and stored iron, while simultaneously enhancing endogenous iron homeostasis, poses a considerable challenge. This study introduces the iron balance dual‐drive strategy (IBDS), which efficiently chelates mitochondrial free iron and promotes ferritin synthesis to create a FerritinBank for iron deposition, thus optimizing endogenous iron homeostasis. IBDS is delivered through an injectable, biodegradable iron‐capturing hydrogel (SilMA/gelMA/DPT). The released DPT selectively targets and chelates free iron within mitochondria, modulating mitochondrial dynamics to restore their function. This action is complemented by the promotion of ferritin synthesis, which serves to bolster endogenous iron homeostasis and suppress ferroptosis. Transcriptomic sequencing and experimental data suggest that DPT corrects energy metabolism abnormalities and promotes mitochondrial macromolecule synthesis. In vivo studies confirm that the iron‐capturing hydrogel significantly improves the healing of smoking‐induced calvarial bone defects. This is the first report of nanoparticles promoting ferritin synthesis to build an endogenous iron reservoir, highlighting the potential of the IBDS strategy for bone regeneration in smokers and other iron‐overload‐related conditions.