Toxicogenomics aims at characterising the mechanism of action (MOA) of environmental exposures, and often relies on transcriptomics to investigate the responses of exposed biological systems. However, the identification of shared toxicogenomics-derived signatures across exposed biological systems is hampered by the complexity and heterogeneity of transcriptomics data. Given the lack of a clear transcriptomic signature of exposure, we hypothesise that common patterns of gene regulation could explain the response to engineered nanomaterials (ENM) across biological systems, disentangling the complexity of their MOA. We performed meta-analysis of a large collection of transcriptomics data from various ENM exposure studies and identified deregulation of immune functions as a prominent response across different ENM exposures. This pattern of transcriptional deregulation differed significantly from exposure to drugs. By investigating the promoter regions of genes frequently altered both in vitro and in vivo following exposure to ENM, we identified a set of binding sites for zinc finger transcription factors C2H2 involved in chromatin remodelling and immunomodulation. We further demonstrate that this gene regulatory model also underlies the transcriptomic MOA in non-mammal species of ecotoxicological interest exposed to ENMs, suggesting that it may be part of the innate immune system conserved by natural selection.