Functional ferritin-mimetic iron homeostasis nanoregulator to suppress ferroptosis and promote angiogenesis as a new therapeutic strategy for diabetic wound healing.

Diabetic foot ulcer (DFU) is among the most severe complications of diabetes, where delayed healing is closely linked to impaired angiogenesis and ferroptosis-associated iron dysregulation. However, the underlying molecular mechanisms remain incompletely understood, and effective interventions specifically targeting DFU healing are still lacking. Here, we present a biomimetic iron homeostasis rebalancing nanoregulator, atRA/GOQDs nanoparticles (RG NPs), designed to rebalance pathological iron dynamics and restore the angiogenic microenvironment in chronic diabetic wounds. RG NPs integrate two complementary regulatory modes: labile iron sequestration mediated by GOQDs and intracellular iron buffering reinforcement through atRA-induced ferritin upregulation. This dual-mode strategy actively reconstructs iron equilibrium, suppresses lipid peroxidation at its source, and inhibits endothelial ferroptosis, thereby facilitating angiogenic function and tissue repair. In vitro, RG NPs exhibited robust labile iron sequestration capacity, enhanced ferritin expression, attenuated ferroptosis injury, and restored endothelial angiogenic activity. In db/db mice, local application of RG NPs significantly accelerated wound closure. Collectively, our work reveals an iron homeostasis-angiogenesis regulatory axis and offers a system-level therapeutic strategy that highlights a conceptual shift from conventional antioxidant and simple iron chelation strategies toward a coordinated iron homeostasis regulation in chronic diabetic wound repair.