Biodegradable Metal–Organic-Frameworks-Mediated Protein Delivery Enables Intracellular Cascade Biocatalysis and Pyroptosis In Vivo

Pyroptosis is a new type of regulated cell death that is of great interest for developing new strategies for treating cancers. This potential is however greatly limited by the low efficiency and selectivity of current strategies to regulate cancer cell pyroptosis. Herein, we report biodegradable metal-organic frameworks (MOFs) for intracellular delivery of glucose oxidase (GOx) that promotes cascade biocatalysis inside cells and selectively induces cancer cell pyroptosis. We show that the self-assembly of Cu²⁺ and 4,4'-azobisbenzoic acid along with GOx affords protein-encapsulated GOx@Cu MOF that efficiently delivers GOx into cells. In addition, the tumor-cell-overexpressed NAD(P)H quinone dehydrogenase 1 (NQO1) can trigger the reduction of 4,4'-azobisbenzoic acid and the degradation of GOx@Cu MOF, releasing GOx to catalyze glucose oxidation and produce excessive hydrogen peroxide (H₂O₂) intracellularly. Furthermore, released Cu²⁺ from Cu MOF could be reduced to Cu⁺ by intracellular glutathione (GSH), promoting Fenton-like reaction with H₂O₂ to continuously generate a hydroxyl radical that induces cancer cell pyroptosis and prohibits tumor cell growth. We anticipate the strategy of harnessing biodegradable MOFs for protein delivery, and intracellular biocatalysis provides a powerful approach to regulate tumor cell pyroptosis for advanced therapeutic development.