IDH-genotype-linked kinase rewiring accompanies enhanced therapeutic response to dual-drug ferritin nanocages in high-grade glioma.

Therapeutic resistance and limited brain penetration remain major challenges in high-grade gliomas. Protein-based nanocarriers, such as the heavy chain of human ferritin (FTH1), facilitate transferrin receptor-mediated transport across the blood-brain barrier. Here, we present multifunctional FTH1 nanocages as a unified nanoplatform for dual-drug chemotherapy and molecular imaging. The nanocages achieve > 98 % gallium-68 labeling efficiency and enable pH-responsive release of doxorubicin and paclitaxel. In isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant tumor models in ovo, FTH1 nanocages exhibit robust intracerebral distribution, tumor accumulation, and enhanced therapeutic efficacy. Dual-drug nanocages significantly reduce tumor growth (p < 0.001), with a stronger effect in the IDH-mutant model (p < 0.001), and improve embryo survival. Kinomic profiling reveals broad suppression of AGC and CMGC kinase families, consistent with attenuation of pro-survival and cell-cycle signaling, particularly in IDH-mutant models. These findings suggest treatment-associated kinase network adaptation linked to the IDH status of the models, consistent with increased therapeutic vulnerability, and support further evaluation of FTH1 nanocages as a platform for improved glioma treatment.