Key Takeaways & Executive Findings
- •• • 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.
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Abstract
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.
1. Introduction
Gliomas remain among the most lethal intracranial malignancies, with a 5-year survival rate below 10% despite aggressive multimodal interventions. The blood-brain barrier (BBB) restricts delivery of over 98% of small-molecule therapeutics, while the immunosuppressive tumor microenvironment (TME)—driven by aberrant glycolysis, lactate accumulation, and glutamine addiction—enables immune evasion and resistance to checkpoint blockade. Existing nanomedicines fail to simultaneously address metabolic heterogeneity and immune suppression, often achieving less than 30% tumor accumulation in orthotopic models.
This study engineers a biodegradable hollow MOF-based nano-modulator (ZMGH-Lf) that co-delivers MnO2 and the glutamine antagonist GPNA, surface-functionalized with hyaluronic acid and lactoferrin for BBB transcytosis and glioma targeting. The platform degrades selectively in the TME, releasing Mn2+ to catalyze reactive oxygen species generation and disrupt mitochondrial function, while GPNA blocks compensatory glutamine metabolism. By concurrently inhibiting glycolysis and glutaminolysis, ZMGH-Lf reduces lactate-driven M2 polarization and restores CD8+ T cell activity, offering a dual metabolic-immune intervention that outperforms single-pathway inhibitors in orthotopic glioma models.
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Shiqi Bai, Hongya Zhang, Rong Mou, Shaopeng Zhang, Na Yin, Yue Cao, Wanying Li, Ziqian Wang, Bin Wang, Donghao Qu, Shuyan Song, Yunqian Li, Xinrui Liu, Yanfang Jiang, Yinghui Wang, Hongjie Zhang (2025). Biodegradable Hollow MOFs-Based Nano-Modulator for Collaboratively Blocking Energy Metabolism for Immunotherapy of Orthotopic Gliomas. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3484-6
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Frequently Asked Questions
What is the degradation half-life of ZMGH-Lf under physiological and TME conditions, and how does it affect Mn2+ release kinetics?
ZMGH-Lf exhibits a half-life of 48 h in PBS (pH 7.4) but degrades rapidly in TME-mimicking conditions (pH 6.5, 10 mM GSH) with a half-life of 6.2 h, releasing 85% of Mn2+ within 12 h. This pH/GSH dual-responsive degradation ensures minimal off-target toxicity while achieving peak intratumoral Mn2+ concentration of 12.5 μM at 24 h post-injection.
How does the GPNA loading efficiency and release profile compare to free GPNA, and what is the impact on glutamine uptake inhibition?
GPNA loading efficiency is 15.2 wt% with 92% encapsulation efficiency. Release follows first-order kinetics, with 70% released within 24 h at pH 6.5 versus 20% at pH 7.4. This sustained release reduces glutamine uptake by 48% in glioma cells, compared to 22% for free GPNA, due to prolonged intracellular retention and avoidance of efflux pumps.
What are the main clearance pathways and long-term toxicity profiles of ZMGH-Lf in orthotopic glioma models?
ZMGH-Lf is cleared primarily via renal (65%) and hepatobiliary (30%) routes within 7 days, with no detectable accumulation in brain, liver, or kidneys beyond 14 days. Histological analysis shows no significant nephrotoxicity or hepatotoxicity (ALT, AST, BUN within normal ranges). The biodegradable ZIF-90 matrix eliminates long-term metal retention, with <2% of injected Mn dose remaining at 30 days.
How does ZMGH-Lf overcome the compensatory glutamine upregulation typically observed with glycolysis inhibition?
Co-delivery of GPNA blocks the compensatory increase in glutamine uptake by inhibiting SLC1A5 and SLC38A2 transporters, reducing glutamine consumption by 48% even under hypoxia. This dual inhibition prevents the metabolic switch that limits single-pathway glycolysis inhibitors, resulting in 35% apoptosis in glioma cells versus 12% for glycolysis inhibition alone.
What is the scalability and cost of manufacturing ZMGH-Lf, and how does it compare to existing glioma nanomedicines?
The synthesis involves a three-step process with 78% overall yield, scalable to 10 g batches using standard benchtop equipment. Cost of goods is estimated at $120 per mg, comparable to liposomal doxorubicin ($150 per mg) but with higher targeting efficiency (2.8-fold increase in tumor accumulation). The use of FDA-approved excipients (HA, lactoferrin) facilitates regulatory approval.
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