Biodegradable Hollow MOFs-Based Nano-Modulator for Collaboratively Blocking Energy Metabolism for Immunotherapy of Orthotopic Gliomas
The immunosuppressive tumor microenvironment (TME) of gliomas renders conventional therapies suboptimal, and aberrant energy metabolism orchestrates tumorigenesis and immune evasion. This work constructs a biodegradable nano-modulator (ZIF-90@MnO2@GPNA, ZMG) based on ZIF-90 decorated with MnO2 and loaded with the glutamine transport antagonist L-γ-glutamyl-p-nitroanilide (GPNA) for glioma therapy via multi-pathway inhibition of energy metabolism and TME reshaping. Hyaluronic acid (HA) and lactoferrin (Lf) are functionalized on the surface (ZMGH-Lf) to cross the blood-brain barrier (BBB) and target gliomas. ZMGH-Lf biodegrades in response to TME stimulation, releasing Mn2+ that catalyzes H2O2 to ·OH, inducing mitochondrial dysfunction. It inhibits glycolysis by alleviating hypoxia and reducing NAD+ expression, while GPNA blocks compensatory glutamine uptake. This strategy achieves multi-pathway disruption of glioma metabolism, relieves immune resistance, and improves the immune TME. Findings demonstrate that ZMGH-Lf effectively inhibits gliomas through multi-way manipulation of energy metabolism and immunotherapy, providing a new strategy for glioma treatment.