Biodegradable Hollow MOFs-Based Nano-Modulator for Collaboratively Blocking Energy Metabolism for Immunotherapy of Orthotopic Gliomas

• • ZMGH-Lf achieves 78.3% tumor growth inhibition in orthotopic glioma models at a dose of 10 mg/kg, with a 2.4-fold increase in median survival compared to untreated controls (p < 0.001), demonstrating clinical potential for overcoming BBB and immunosuppression. • • The nano-modulator releases Mn2+ at 12.5 μM within 24 h under TME-mimicking conditions (pH 6.5, 10 mM GSH), catalyzing H2O2 to ·OH with a rate constant of 0.45 s−1, which induces mitochondrial dysfunction and reduces ATP production by 62% in glioma cells. • • Glycolysis inhibition via ZMGH-Lf reduces lactate secretion by 54% and downregulates HIF-1α expression by 70%, leading to decreased M2 macrophage polarization (CD206+ cells from 45% to 18%) and enhanced CD8+ T cell infiltration (2.8-fold increase). • • GPNA loading (15.2 wt%) blocks compensatory glutamine uptake, reducing glutamine consumption by 48% and inducing 35% apoptosis in glioma cells under hypoxic conditions, addressing metabolic plasticity that limits single-pathway inhibitors.