The MS2 system takes advantage of the ability of the bacteriophage MS2 coat protein (MCP) to bind to an aptamer sequence (known as the MS2 aptamer) with high specificity and affinity (Figure 1B, Table 1) , , , . To enable single-RNA imaging, target RNA is genetically modified to harbor multiple tandem repeats of the MS2 aptamer. When co-expressed with an MCP-GFP fusion protein, each target RNA can then be tagged by multiple GFPs through MS2-MCP interactions, thus appearing as a bright fluorescent spot. To date, the MS2 system has been the most popular approach for imaging single engineered RNA transcripts in living cells, owing to its biostability and ease of delivery , , , , . However, this approach cannot be used for imaging endogenous RNAs, and its use of fluorescent proteins limits fluorophore brightness that is necessary for high-quality imaging. Furthermore, MCP-GFP fusion proteins weigh nearly 40 kDa. Thus binding of multiple large probes to an RNA may potentially interfere with its normal activities and functions .