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

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.