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.

Effects of Two Kinds of Iron Nanoparticles as Reactive Oxygen Species Inducer and Scavenger on the Transcriptomic Profiles of Two Human Leukemia Cells with Different Stemness

“…This previous study and this study all revealed that the treatment of Fe 3 O 4 nanoparticles induced lipid accumulation in cells. In consistence with the previous study [ 36 ], this study also found that several lipid synthesis-related genes were upregulated in HF, including FDFT1, ACAT2, and HMGCS1. In contrast, the most significant biological process was myeloid leukocyte activation and cation homeostasis in the PBNP-treated HL60 cells ( Figure 4 C,D).…”

“…This gene was also upregulated in HF and HP. This kind of significant effect of FeNPs on lipid metabolism was also found in the HepG2 cell treated by Fe 3 O 4 nanoparticles in a previous study [ 36 ]. This previous study and this study all revealed that the treatment of Fe 3 O 4 nanoparticles induced lipid accumulation in cells.…”

“…In agreement with the downregulation of CD38, the significant upregulation of Ly6E in the two FeNP-treated leukemia cells also suggested that FeNPs preferentially killed non-stemness leukemia cells and thus allowed the proportion of stemness leukemia cells to increase in live cells. These data suggested the resistance of LSC to iron nanoparticle-induced cell death such as ferroptosis and nanoptosis [ 36 ].…”

Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington’s Like Disorder in Preclinical Model

“…Since the discovery of first iron-containing nanozyme in last decade 4 , numerous nanomaterials have been elucidated to have oxidase 5 , catalase 6 , SOD 7,8 , peroxidase 9 , monooxygenase 10 , hydrolase 11 , laccase 12 mimicking activities and therefore been used in diverse applications like the destruction of biofilm, removal of algal bloom, immunoassay, tissue staining, cancer treatment, and glucose biosensing. However, despite being the most promising candidate as catalytic biomedicine, the clinical translation of nanozymes for therapeutic usage is still lacking [13][14][15] . Inherent toxicity of the materials used in the preparation of contemporary nanozymes, low aqueous solubility, inability to properly function in the physiological milieu, lack of selectivity (towards biological substrate), and incompatibility with other enzymes in catalyzing intracellular cascade reactions are considered to be the confounding factors [15][16][17][18] .…”

“…Combination of the observed behavioral features indicated that the anxiety was induced due to severe 3-NPA neurotoxicity, which was ameliorated upon treatment with C-Mn 3 O 4 nanozymes. Light [12] preference test was further used to validate our observations about the anxiolytic effects of replaced with a novel object, and the animals were permitted another 2 mins of exploration [13] time. Their time of interaction with each of the two objects were measured during the experimental period (Supplementary Figure S6a).…”