In Situ Ferroptosis with Global Dynamics Visualization for Glioblastoma Theranostics

Glioblastoma Multiforme (GBM) remains a lethal cancer due to its invasive nature and limited treatment options. We present 1-ethyl-2-((E)-2-((E)-3-(2-((E)-1-ethyl-3,3-dimethylindolin-2-ylidene)ethylidene)-2-(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)phenoxy)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium (CDI), a near-infrared (NIR) activatable theranostic probe that integrates tumor detection, in situ ferroptosis induction, and treatment monitoring. CDI selectively activates in the GBM tumor microenvironment (H₂O₂ >30 μM) via boronate ester cleavage, enabling precise cancer discrimination. Upon activation, CDI releases diacetic acid (MDA) that chelates endogenous Fe³⁺ in situ, driving localized Fenton reactions to induce ferroptosis without systemic iron supplementation. A concurrent ratiometric fluorescence shift (675 → 750 nm) provides potential real-time feedback on treatment efficacy. Transcriptomic analysis verified ferroptosis as the primary cell death mechanism, with significant dysregulation of iron/lipid metabolism pathways. In vitro and in vivo studies demonstrated blood-brain barrier (BBB) penetration, tumor-specific accumulation, inhibition of glioma cell migration/invasion, and extended survival in GBM models with no major adverse effects. CDI establishes a transformative "see-treat-confirm" paradigm for GBM surgery.