Biodegradable hollow MOFs-based nano-modulator for collaboratively blocking energy metabolism for immunotherapy of orthotopic gliomas

The immunosuppressive tumor microenvironment (TME) of gliomas makes their treatment consistently suboptimal, and the aberrant energy metabolism of glioma cells orchestrates tumorigenesis and the immunosuppressive TME. In this work, we construct a biodegradable nano-modulator (ZIF-90@MnO₂@GPNA, ZMG) based on ZIF-90 decorated by MnO₂ and loaded with glutamine transport antagonist (L-γ-glutamyl-p-nitroanilide, GPNA) for efficiently gliomas therapy by multi-pathways inhibition of energy metabolism and reshaping TME. In order to efficiently cross the blood-brain barrier (BBB) and target the gliomas, hyaluronic acid (HA) and lactoferrin (Lf) are further functionalized on its surface (ZIF-90@MnO₂@GPNA@HA-Lf, ZMGH-Lf). ZMGH-Lf biodegrades in response to stimulation of TME, releasing Mn²⁺, which can catalyze H₂O₂ to ·OH and lead to mitochondrial dysfunction. ZMGH-Lf can inhibit glycolysis by alleviating hypoxia and reducing NAD⁺ expression, while loaded GPNA inhibits the compensatory increase in glutamine uptake. This therapeutic strategy not only achieves a multi-pathway disruption of glioma metabolism, but also relieves the immune resistance and improves the immune TME. All these findings demonstrate that ZMGH-Lf can effectively inhibit gliomas by multi-ways manipulation of energy metabolism and immunotherapy, which provides a new strategy for the treatment of gliomas.