H-ferritin engineered nanoplatform reprograms metabolism and immunity for glioblastoma immunotherapy

Disrupting mitochondrial metabolism and reactivating antitumor immunity offers a compelling strategy to enhance therapeutic outcomes in glioblastoma (GBM). Here, we report a mitochondria-targeting nanoplatform that integrates GBM-selective delivery, metabolic disruption, and immune activation for synergistic GBM therapy. The nanoplatform co-encapsulates L820-a conjugate of lonidamine (LND) and IR820 with mitochondrial affinity-and the immunomodulator TP5 into a ZIF-8 framework, which is coated with H-ferritin (HFn) for TfR1-mediated blood-brain barrier (BBB) penetration and GBM targeting. After endocytosis and GBM-specific, acid-triggered degradation, L820 accumulates in mitochondria and causes profound mitochondrial dysfunction, including membrane potential collapse, ATP depletion, and AMPK activation. Concurrently, Zn²⁺ released from ZIF-8 suppresses GLUT1 and HIF-1α, impairing glycolysis and reducing CD47 expression. These dual metabolic stresses induce mitochondrial DNA (mtDNA) release and activate the cGAS-STING pathway, promoting type I interferon production and immunogenic cell death. TP5 enhances T cell activation while suppressing Tregs, further remodeling the GBM immune microenvironment. This mitochondria-focused strategy achieves potent metabolic interference and immune reprogramming for effective GBM treatment.