Peroxidase‐Like Nanozymes Induce a Novel Form of Cell Death and Inhibit Tumor Growth In Vivo

Abstract Nanomaterials with intrinsic enzyme‐like properties, termed nanozymes, have attracted significant interest, although limited information is available on their biological characteristics in cells or in vivo. Here, it is shown that nanomaterials with peroxidase‐like activity trigger a novel form of cell death through an ATP‐citrate lyase (ACLY)‐dependent rat sarcoma viral oncogene (RAS) signaling mechanism. The peroxidase nanozyme‐induced cell lethality, which is termed as nanoptosis, is morphologically and biochemically distinct from the currently well‐defined apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis. It is revealed that nanoptosis is typically characterized by the massive accumulation of cellular vesicles, swelling mitochondria, and distinct chromatin condensation and margination. Using RNA sequencing and protein quantitative mass spectrometry, an ACLY‐dependent RAS signaling pathway is identified that mainly mediates this nanozyme lethality process, and it is observed that RAS‐knockout cells are highly resistant to nanoptosis. Finally, it is demonstrated that this newly discovered nanozyme lethality can be used as an effective therapeutic strategy for inhibiting tumor growth in vivo.