Imbalanced redox homeostasis, involving either oxidative stress or reductive stress, can profoundly impact cellular functions, contributing to various diseases. While the implications of oxidative stress in the adverse effects of nanoparticles have been extensively studied, our comprehension of reductive stress within the context of nano-redox system interactions remains limited. Here we illuminate a domino effect initiated by the dehydrogenase-like activity of transition metal borides. Specifically, seven transition metal borides were identified to emulate the enzymatic activity of natural dehydrogenases, resulting in heightened levels of reductive constituents within critical biological redox pairs in cells. Mass cytometry analysis provides compelling evidence that reductive stress initiates an immunosuppressive environment within lung tissues, promoting the metastasis of breast cancer cells to the lungs. In summary, our study unveils the chemical basis of nano-induced reductive stress and establishes a mechanistic axis that interlinks dehydrogenase-like activity, reductive stress, immunosuppression and tumour metastasis.

Nanotechnology Centre Centre for Energy and Environmental Technologies VSB Technical University of Ostrava Ostrava Poruba Czech Republic

New Cornerstone Science Laboratory Laboratory of Theoretical and Computational Nanoscience National Center for Nanoscience and Technology University of Chinese Academy of Sciences Beijing China

School of Public Health Soochow University Suzhou China

Sino Danish College Sino Danish Center for Education and Research University of Chinese Academy of Sciences Beijing China

State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection School for Radiological and Interdisciplinary Sciences Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Suzhou Medical College Soochow University Suzhou China

See more in PubMed

Vardhana, S. A. et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21, 1022–1033 (2020). PubMed DOI PMC

Lee, C. et al. Analysing the mechanism of mitochondrial oxidation-induced cell death using a multifunctional iridium(III) photosensitiser. Nat. Commun. 12, 3484 (2021).

Wiederkehr, A. & Demaurex, N. Illuminating redox biology using NADH- and NADPH-specific sensors. Nat. Methods 14, 671–672 (2017). PubMed DOI

Circu, M. L. & Aw, T. Y. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic. Biol. Med. 48, 749–762 (2010). PubMed DOI PMC

Cracan, V., Titov, D. V., Shen, H., Grabarek, Z. & Mootha, V. K. A genetically encoded tool for manipulation of NADP PubMed DOI PMC

Peoples, J. N. et al. Mitochondrial dysfunction and oxidative stress in heart disease. Exp. Mol. Med. 51, 1–13 (2019). PubMed DOI

Butterfield, D. A. & Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci. 20, 148–160 (2019). PubMed DOI PMC

Laforge, M. et al. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat. Rev. Immunol. 20, 515–516 (2020). PubMed DOI PMC

Manford, A. G. et al. A cellular mechanism to detect and alleviate reductive stress. Cell 183, 46–61 (2020). PubMed DOI

Xiao, W. & Loscalzo, J. Metabolic responses to reductive stress. Antioxid. Redox Signal. 32, 1330–1347 (2020). PubMed DOI PMC

Cai, X. et al. Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation. Part. Fibre Toxicol. 14, 13 (2017). PubMed DOI PMC

Li, R. et al. Surface oxidation of graphene oxide determines membrane damage, lipid peroxidation, and cytotoxicity in macrophages in a pulmonary toxicity mode. ACS Nano 12, 1390–1402 (2018). PubMed DOI PMC

Liu, C. et al. Arsenene nanodots with selective killing effects and their low-dose combination with β-elemene for cancer therapy. Adv. Mater. 33, 2102054 (2021). DOI

Gan, S. et al. Size optimization of organic nanoparticles with aggregation-induced emission characteristics for improved ROS generation and photodynamic cancer cell ablation. Small 18, 2202242 (2022). DOI

Yang, B. et al. Intratumoral synthesis of nano-metalchelate for tumor catalytic therapy by ligand field-enhanced coordination. Nat. Commun. 12, 3393 (2021). PubMed DOI PMC

Sun, J. et al. Nanoparticles and photochemistry for native-like transmembrane protein footprinting. Nat. Commun. 12, 7270 (2021). PubMed DOI PMC

Ding, B. et al. Sodium bicarbonate nanoparticles for amplified cancer immunotherapy by inducing pyroptosis and regulating lactic acid metabolism. Angew. Chem. Int. Ed. 135, 202307706 (2023). DOI

Bao, W. et al. MOFs-based nanoagent enables dual mitochondrial damage in synergistic antitumor therapy via oxidative stress and calcium overload. Nat. Commun. 12, 6399 (2021). PubMed DOI PMC

Jia, Q. et al. Mitochondrial hydrogen peroxide positively regulates neuropeptide secretion during diet-induced activation of the oxidative stress response. Nat. Commun. 12, 2304 (2021). PubMed DOI PMC

Zhang, Y. et al. Upregulation of antioxidant capacity and nucleotide precursor availability suffices for oncogenic transformation. Cell Metab. 33, 94–108 (2021). PubMed DOI

Christians, E. S. & Benjamin, I. J. Proteostasis and REDOX state in the heart. Am. J. Physiol. Heart Circ. Physiol. 302, 24–37 (2012). DOI

Xi, Z. et al. Nickel–platinum nanoparticles as peroxidase mimics with a record high catalytic efficiency. J. Am. Chem. Soc. 143, 2660–2664 (2021). PubMed DOI

Manoj, K. M. et al. Murburn precepts for lactic-acidosis, Cori cycle, and Warburg effect: interactive dynamics of dehydrogenases, protons, and oxygen. J. Cell. Physiol. 237, 1902–1922 (2022). PubMed DOI

Li, Q. et al. Revealing activity trends of metal diborides toward pH-universal hydrogen evolution electrocatalysts with Pt-like activity. Adv. Energy Mater. 9, 1803369 (2019). DOI

Ai, X. et al. Transition-metal–boron intermetallics with strong interatomic d–sp orbital hybridization for high-performance electrocatalysis. Angew. Chem. Int. Ed. 59, 3961–3965 (2020). DOI

Croft, D. P. et al. The effect of air pollution on the transcriptomics of the immune response to respiratory infection. Sci. Rep. 11, 19436 (2021). PubMed DOI PMC

Xu, S. et al. Vacancies on 2D transition metal dichalcogenides elicit ferroptotic cell death. Nat. Commun. 11, 3484 (2020). PubMed DOI PMC

Marcais, A. & Walzer, T. An immunosuppressive pathway for tumor progression. Nat. Med. 24, 260–261 (2018). PubMed DOI

Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 548–524 (2005). DOI

Dubrot, J. et al. In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer. Nat. Immunol. 23, 1495–1506 (2022). PubMed DOI

Rajasekaran, N. S. et al. Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Antioxid. Redox Signal. 14, 957–971 (2011). PubMed DOI PMC

Dialynas, G. et al. Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway. PLoS Genet. 11, 1005231 (2015). DOI

Zhang, X. et al. Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension 55, 1412–1417 (2010). PubMed DOI

Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015). PubMed DOI PMC

Ge, M., Papagiannakopoulos, T. & Bar-Peled, L. Reductive stress in cancer: coming out of the shadows. Trends Cancer 10, 103–112 (2024). PubMed DOI

Talwar, D. et al. The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells. Nat. Metab. 5, 660–676 (2023). PubMed DOI PMC

Wiel, C. et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 178, 330–345 (2019). PubMed DOI

Kashif, M. et al. ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis. Redox Biol. 60, 102619 (2023). PubMed DOI PMC

Gao, M. et al. Nano-enabled quenching of bacterial communications for the prevention of biofilm formation. Angew. Chem. Int. Ed. 135, 202305485 (2023). DOI

Wu, D. et al. Engineering Fe–N doped graphene to mimic biological functions of NADPH oxidase in cells. J. Am. Chem. Soc. 142, 19602–19610 (2020). PubMed DOI

Liu, X. et al. Doped graphene to mimic the bacterial NADH oxidase for one-step NAD PubMed DOI

Gao, M. et al. Engineering catalytic dephosphorylation reaction for endotoxin inactivation. Nano Today 44, 101456 (2022). DOI

Xie, Q. et al. Discovery of lipoxygenase-like materials for inducing ferroptosis. ACS Nano 18, 32438–32450 (2024). PubMed DOI

Liu, X. et al. Exploring nanozymes for organic substrates: building nano-organelles. Angew. Chem. Int. Ed. 63, 202408277 (2024). DOI

Han, G. et al. Metal-isotope-tagged monoclonal antibodies for high-dimensional mass cytometry. Nat. Protoc. 13, 2121–2148 (2018). PubMed DOI PMC

Genetic modulation of rare earth nanoparticle biotransformation shapes biological outcomes

Multimodal feature fusion machine learning for predicting chronic injury induced by engineered nanomaterials