biostudies-literatureUnknown23(1)Liu SFerroptosis 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) Fe<supJournal of nanobiotechnology605https://www.ebi.ac.uk/biostudies/studies/S-EPMC12465256biostudies-literatureQuadruple synergistic amplification of ferroptosis for precision glioblastoma therapy: a luteolin-coordinated ferric ion nanoplatform.PMC12465256Liu XChang YXWang PWang BPeng BYu XALiu SLi MSun KfalseQuadruple 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) Fe<sup2025-01-01T00:00:00Z2025 Sep2026-06-03T21:23:29.935Z2026-05-01T03:11:06.501ZS-EPMC124652564099946910.1186/s12951-025-03688-1