Magneto-NIR-II-Programmed Cascade Nanozymes Unlocking Blood-Brain Barrier Translocation and Autophagic Resistance in...

Glioblastoma (GBM) remains a highly aggressive central nervous system malignancy, and its treatment is hindered by poor drug accumulation across the blood-brain barrier (BBB) and autophagy-mediated repair. To address these barriers, rare-earth-doped Nd_0.02Fe_2.98S₄@HA nanozymes (NFSH) are constructed as magneto-NIR-II-programmed cascade nanozymes for trans-BBB delivery, multimodal imaging, and ferroptosis amplification. Hyaluronic acid (HA)-mediated CD44 targeting and oriented magnetic field-enhanced BBB permeability promote tumor enrichment, while Nd³⁺ doping endows NFSH with strengthened superparamagnetism, near-infrared second window (NIR-II) photodynamic activity, and NIR-II fluorescence capability. Under alternating magnetic field (AMF) and NIR-II laser stimulation, NFSH activates catalase-, peroxidase-, glutathione oxidase-, and nicotinamide adenine dinucleotide (NADH) oxidase-like cascade catalysis, which amplifies reactive oxygen species (ROS) production, consumes glutathione, and induces ferroptosis. In the acidic tumor microenvironment, AMF further promotes H₂S release, disrupts lysosomal autophagic degradation, and aggravates mitophagy inhibition through NADH depletion-mediated ATP deficiency. This cascade mechanism enhances ferroptosis and reshapes the tumor immune microenvironment by relieving hypoxia and promoting M2-to-M1 macrophage polarization. In addition, NFSH enables NIR-II fluorescence and T₂-weighted magnetic resonance imaging for real-time visualization of treatment. This strategy provides an integrated trans-BBB theranostic platform for autophagy-suppressed ferroptosis therapy against GBM.