Circular RNAs (circRNAs) are recently identified as a naturally occurring family of widespread and diverse endogenous noncoding RNAs that may regulate gene expression in mammals1,2,3,4. They are unusually stable RNA molecules with cell type- or developmental stage-specific expression patterns3,5. Exosomes are small membrane vesicles of endocytic origin secreted by most cell types. They contain a specific cargo of protein, mRNA and microRNA species, which can modulate recipient cell behaviors and may be used as biomarkers for diagnosis of human diseases6. Here, we show for the first time the presence of abundant circRNAs in exosomes. RNA-seq analyses revealed that circRNAs were enriched in exosomes compared to the producer cells. Furthermore, the sorting of circRNAs to exosomes may be regulated by changes of associated miRNA levels in producer cells, and may transfer biological activity to recipient cells. Additionally, more than 1 000 circRNAs were identified in human serum exosomes. circRNAs originated from human cancer xenografts could enter the circulation and be readily measured in the serum. Intriguingly, serum exosomal circRNAs were able to distinguish patients with colon cancer from healthy controls. Our results lay the foundation for development of circRNAs as a new class of exosome-based cancer biomarkers and suggest the potential biological function of exosomal circRNAs.

circRNA has been reported to be able to bind to miRNA, which is also shown to be abundant in exosomes. This prompts us to investigate the relation of circRNA and miRNA, regarding the sorting of circRNA to exosomes. As CDR1as circRNA is known to act as a miR-7 sponge1,3, we introduced miR-7 mimics into cells and determined the level of CDR1as in cells and exosomes. Interestingly, we observed that the level of CDR1as circRNA was significantly downregulated in exosomes, but slightly increased in cells, upon ectopic expression of miR-7 in both HEK293T and MCF-7 cells (Figure 1E and Supplementary information, Figure S7). This result suggests that sorting of circRNAs to exosomes was regulated, at least in part, by changes of associated miRNA levels in producer cells. Furthermore, we found that exo-circRNA retained biological activity as the CDR1as exosomes could abrogate miR-7-induced growth suppression in receipt cells (Figure 1F).

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