# Biomimetic sequentially gated nanotuners based on amorphous metal–organic frameworks for reprogramming the metabolism-ferroptosis-immunity crosstalk in gliomas

## TL;DR

A new nanotuner (ZB@HM) reprograms glioma metabolism and immunity to enhance ferroptosis and antitumor immunity.

## Contribution

A biomimetic sequentially gated nanotuner that modulates metabolism-ferroptosis-immunity crosstalk in gliomas.

## Key findings

- ZB@HM triggers ferroptosis and immunogenic cell death via NADPH and cysteine depletion.
- Methionine restriction by ZB@HM suppresses tumor cysteine biosynthesis and enhances T-cell methionine uptake.
- Treatment with ZB@HM downregulates immune checkpoints and reverses T-cell exhaustion.

## Abstract

Glioma's metabolic reprogramming fortifies antioxidant defenses and fosters an immunosuppressive microenvironment, thus resulting in robust resistance to ferroptosis-immunotherapy. In this study, a biomimetic sequentially gated amorphous MOF-based nanotuner (ZB@HM) was constructed, which could cascade depletion of metabolic substrates of ferroptosis defense and redistribution of methionine for reprogramming metabolism-ferroptosis-immunity crosstalk. Specifically, we engineered a methionine-inhibitor-loaded amorphous ZIF-82, followed by coating with E. coli-glioma hybrid membrane to improve its blood-brain barrier penetration and gliomas-targeting. The amorphous MOF undergoes acidic-triggered disintegration, releasing 2-nitroimidazole that is selectively activated via NADPH reduction in hypoxia. The activated ligand subsequently covalently binds with thiol-containing cysteine. The cascade depletion of NADPH and cysteine, synergizing with Zn2+ overload, effectively triggers robust ferroptosis and immunogenic cell death. Moreover, ZB@HM selectively restricts methionine uptake in gliomas, suppressing the transsulfuration pathway for cysteine biosynthesis and enhancing the competitive uptake of methionine by T cells. The reduced intracellular methionine pool in gliomas diminishes S-adenosylmethionine biosynthesis, downregulating immune checkpoint expression. This cascade reverses T-cell exhaustion and reinforces antitumor immunity. RNA sequencing analysis revealed that treatment with ZB@HM resulted in a modulation of gene signatures associated with the GSH metabolism and tumor immunotherapy. Collectively, ZB@HM reprograms the metabolism-ferroptosis-immune crosstalk through orchestrating multiple key metabolites.

This study synthesizes a biomimetic sequentially gated (acidity-hypoxia responsive) MOF-based nanotuner (ZB@HM) that remodels immunosuppressive microenvironment by reprogramming metabolism-ferroptosis-immunity crosstalk network. Mechanistically, ZB@HM undergoes acid-mediated degradation, releasing 2-nitroimidazole, which disrupts ferroptosis defense via hypoxia-responsive NADPH/cysteine cascade depletion. Released methionine uptake inhibitors selectively restricts tumor's methionine supply, potentiating ferroptosis, downregulating immune checkpoints and reversing T-cell exhaustion.Image 1