miRNAs in Protein Complexes
Using differential centrifugation and size exclusion chromatography, Arroyo et al. (Arroyo et al. 2011) demonstrated the presence of miRNA and Ago2 complexes in the circulation that were not encapsulated in membrane-bound vesicles. Surprisingly, two populations of circulating miRNAs were identified. While the majority of the miRNAs were copurified with cell-free Ago2 complexes, there was a minority of miRNAs such as let-7a that associated predominantly with vesicles (Arroyo et al. 2011). Apart from Ago2, other members of the Argonaute family (Ago1) were also reported to associate with miRNAs in the circulation (Turchinovich et al. 2011). Nucleophosmin (NPM1), an RNA-binding protein, was also identified in the conditioned medium of fibroblasts to form complexes that protect miRNAs from degradation, although the mechanism of action is not well understood (Wang et al. 2010).
miRNAs in Lipoprotein Complexes
The presence of a stable miRNA pool in lipoprotein complexes in the circulation has also been described. Within the high-density lipoprotein (HDL), miRNA complexes were detected, and delivery to recipient cells was shown to occur in a scavenger receptor class B type I-dependent manner (Vickers et al. 2011). A follow-up study demonstrated delivery of functional miRNAs that regulate gene expression in the recipient cells. HDL-mediated transport of miR-223 to endothelial cells was shown to suppress the expression of intercellular adhesion molecule 1(ICAM-1). The transport of miRNA could account for the anti-inflammatory properties of HDL at least partially (Tabet et al. 2014). Interestingly, Wagner et al. reported that no transfer of miRNAs via HDL complexes to endothelial cells could be detected (Wagner et al. 2013), suggesting this transport mechanism is not as universal as initially thought and may occur only under defined conditions.