On-demand biocatalytic dual oxygen spray reprograms the hypoxia-ferroptosis axis to accelerate chronic wound healing

Effective clinical management of chronic hypoxic wounds remains challenging due to persistent hypoxic signaling, oxidative stress, and cellular dysfunction. Hypoxia-induced ferroptosis has recently gained attention as a key molecular driver of impaired healing in chronic wounds such as ischemic and diabetic wounds. Herein, a bioinspired self-oxygenating dual spray incorporating silk fibroin, aloe vera mucilage, and hemoglobin in the primary SAH spray and hydrogen peroxide in the secondary Hp spray is developed. Upon application, the dual oxygenation spray (SAH-Hp) triggers peroxide-responsive instantaneous O₂ release through the biocatalytic activity of hemoglobin. Localized O₂ generation alleviates hypoxia and restores redox and iron homeostasis, thereby interrupting the hypoxia-driven ferroptotic cascade. Mechanistic investigations demonstrate that sustained oxygenation suppresses lipid peroxidation, limits iron overload, and enhances antioxidant defenses through restoration of the GSH-GPX4 antioxidant defense. Consequently, the SAH-Hp spray promotes angiogenic regeneration and tissue repair under pathological hypoxic conditions. Extensive preclinical validation in rabbit ear ischemic wounds and streptozotocin-induced diabetic wounds confirms accelerated healing accompanied by reduced hypoxic stress and ferroptosis regulation. Collectively, the on-demand SAH-Hp spray facilitates localized O₂ generation as an effective strategy for managing chronic wounds by targeting the hypoxia-ferroptosis axis, providing a clinically translatable oxygenation platform for next-generation regenerative wound therapies.