Quadruple synergistic amplification of ferroptosis for precision glioblastoma therapy: a luteolin-coordinated ferric ion nanoplatform

Ferroptosis is emerging as a promising therapeutic strategy for glioblastoma (GBM). However, insufficient lipid peroxidation levels and blood-brain barrier (BBB) pose a significant challenge for GBM treatment. Here, we present natural product luteolin (Lut)-coordinated Fe³⁺ nanoparticles loaded with dihydroartemisinin (DHA), designated as FLD NPs, which can cross the BBB and induce quadruple amplified ferroptosis. Specifically, FLD NPs leverage four mechanisms to enhance ferroptosis: (1) Lut upregulates heme oxygenase 1 (HO-1), promoting heme degradation and recruiting endogenous Fe²⁺. (2) exogenous Fe³⁺ depletes glutathione (GSH), increasing Fe²⁺ levels and catalyzing H₂O₂ to generate ·OH via the Fenton reaction; (3) Fe²⁺ facilitates the cleavage of DHA's peroxide bridge, further elevating ·OH production; and (4) Lut-coordinated Fe³⁺ acts as a photothermal agent, accelerating the Fenton reaction under light irradiation. Furthermore, FLD NPs enable multimodal imaging capabilities, including photoacoustic and photothermal imaging, for precise tumor targeting. It demonstrates satisfactory antitumor efficacy in GBM models, highlighting its potential as a novel ferroptosis-amplifying nanotherapeutic. Importantly, this study reveals that Lut modulates tight junction protein expression in vascular endothelial cells, facilitating BBB penetration. This work highlights a novel strategy for GBM therapy, leveraging natural product-mediated nanoparticles to amplify ferroptosis.