Mitochondria-targeting nano therapy altering IDH2-mediated EZH2/EZH1 interaction as precise epigenetic regulation in glioblastoma

Glioblastoma (GBM) is a complex brain cancer with frequent relapses and high mortality and still awaits effective treatment. Mitochondria dysfunction is a pathogenic condition in GBM and could be a prime therapeutic target for ceasing GBM progression. Strategies to overcome brain solid tumor barriers and selectively target mitochondria within specific cell types may improve GBM treatment. Here, we present hypericin-conjugated gold nanoparticles (PEG-AuNPs@Hyp) where hypericin is a mitochondrion-targeting agent exhibiting multimodal therapy by critically impacting the IDH2 gene (Isocitrate dehydrogenase) and its interaction with polycomb methyltransferase EZH1/2 for GBM therapy. It significantly localizes in mitochondria by enhanced cellular uptake in the human GBM cell lines/three-dimensional (3D) culture model under red-light exposure. It triggers oxidative stress and changes the mitochondrial potential, with increased Bax/Bcl2 ratio enhancing GBM cell death. The suppressed expression of mutated IDH2 and polycomb group of proteins upon PEG-AuNPs@Hyp/light exposure regulates mitochondria-targeting-mediated GBM metabolism with epigenetic repression of complex machinery function. Polyubiquitination and proteasomal degradation of EZH1 indicate the implication of these polycomb proteins in GBM progression. Chromatin immunoprecipitation reveals the IDH2 and EZH1/EZH2 direct interaction, confirming the role played by IDH2 in modulating the expression of EZH1 and EZH2. In vivo studies further displayed better tumor ablation in a GBM tumor-bearing nude mouse model. The present multimodal nanoformulation compromised the functional dependency of polycomb on mitochondrial IDH2 and established the mechanism of GBM inhibition.