Light-triggered carbon monoxide-induced activation of enhanced ferritinophagy-mediated ferroptosis for bone metastases therapy

Bone metastases, as a common disabling and life-threatening complication in the advanced stages of various solid tumors, continue to pose substantial therapeutic challenges due to high drug toxicity and tumor resistance. To overcome the limited efficacy and safety concerns of existing treatments, we developed a novel iron-based photocatalytic nanoplatform (ENCF), guided by second near-infrared (NIR-II) imaging, for the precise treatment of bone metastases. This platform enables in situ photocatalytic release of CO and utilizes exposed iron active sites to synergistically induce ferroptosis through a cascade of oxidative stress, autophagy and iron metabolism disruption under 808 nm laser activation. Mechanistic investigations revealed that the ENCF platform significantly downregulates PCBP2, a key regulator of ferritinophagy, while activating LC3- and ATG5-mediated autophagic pathways to accelerate FTH1 degradation and Fe²⁺ release, thereby disturbing intracellular iron homeostasis. Concurrently, the released CO disrupts mitochondrial electron transport and inhibits ATP synthesis, leading to excessive ROS accumulation, enhanced suppression of GPX4 , accelerated lipid peroxidation, and the initiation of a robust ferroptotic response. Benefiting from its deep-tissue photoactivation, high catalytic efficiency, and multi-target synergistic mechanisms, ENCF achieved potent tumor suppression with selective accumulation at metastatic sites in a bone metastasis model. Collectively, this study establishes a multi-pronged therapeutic strategy via "CO release-autophagy enhancement-ferroptosis activation," offering a promising and innovative approach for the precise treatment of bone metastases.