Circular RNAs (circRNAs) play important roles in regulating various biological processes; however, their roles in regulating the toxicity of engineered nanomaterials (ENMs) are still unclear. Based on Illumina HiSeq2500 sequencing, we here identified 43 dysregulated circRNAs in graphene oxide (GO) (1 mg L) exposed nematodes. Five of these candidate circRNAs could be further dysregulated by GO exposure in the range of μg L. Using the RNA interference (RNAi) technique, we found that the alteration in expressions of , and mediated a protective response to GO exposure; however, the alteration in expressions of and mediated the toxicity induction of GO. In nematodes, the acted in certain tissues (intestine and neurons) to regulate GO toxicity. Moreover, an intermediate filament protein IFC-2 required for intestinal development was identified as a target of in regulating the GO toxicity. In the intestine, intestinal IFC-2 acted further upstream of FOXO transcriptional factor DAF-16 in the insulin signaling pathway to regulate the GO toxicity. Therefore, intestinal in the signaling cascade of -IFC-2-DAF-16 regulates the GO toxicity by modulating the function of IFC-2.