NIR-elicited nanoplatform amplifies cancer ferrotherapy in uveal melanoma via synergistic ferroptosis induction and glucose metabolism intervention.

Uveal melanoma (UM), the most prevalent primary intraocular malignancy in adults, is characterized by high metastatic potential, with no therapies shown to improve overall survival. This underscores the critical need for exploring new treatment approaches. Ferroptosis has become a promising therapeutic approach in cancer therapy. However, metabolic reprogramming of tumor cells frequently upregulates antioxidative defense by enhancing antioxidant synthesis, thus constraining the effectiveness of ferroptosis. In this study, we have developed a pH/near-infrared (NIR)-responsive nanoplatform that co-loads ferric ions and the hypoxia-inducible factor-1 (HIF-1) inhibitor acriflavine (ACF), aiming to potentiate iron-based ferrotherapy through modulation of glucose metabolism. Upon release, ferric ions are reduced intracellularly to ferrous ions by glutathione (GSH). The resultant ferrous ions subsequently catalyze Fenton reactions that produce hydroxyl radicals (•OH), ultimately triggering ferroptosis. Concurrently, HIF-1-mediated metabolic reprogramming is suppressed by ACF. The resulting inhibition of glycolysis and the pentose phosphate pathway curtailed ATP and NADPH supply, resulting in impairment of the GSH/glutathione peroxidase 4 defense system and thus enhancing tumor susceptibility to ferroptosis. In addition, the excellent NIR absorption efficiency of MPDA enables photoacoustic imaging-guided treatment monitoring as well as efficient photothermal therapy (PTT). The PTT further enhanced drug release and accelerated the Fenton reaction, resulting in a cascade amplification of therapeutic efficacy against UM. Collectively, our study establishes a synergistic therapeutic strategy that integrates glycometabolism-intervention-enhanced ferroptosis with PTT, presenting a powerful and versatile approach for UM treatment.