Conventional MBs, including those that are synthesized with backbones composed of DNA or 2Me RNA linked with phosphodiester bonds (DNA or 2Me MBs), can be highly sensitive to nuclease degradation. To confer nuclease resistance, a non-bridging oxygen of the phosphate may be replaced with a sulfur atom to form a chemically-modified internucleotide linkage known as the PS bond. Yeh et al. reported the first use of MBs that incorporate PS linkages throughout the probe backbone (2Me/PSFULL MBs) and showed that these MBs enable detection of Coxsackie viral RNA replication for up to 12 h . Supporting this finding, we showed that 2Me/PSFULL MBs have longer intracellular stability and bioactivity than 2Me MBs . Despite these attributes, however, we found that 2Me/PSFULL MBs still cause a detectable FPS . Several hours after entry, 2Me/PSFULL MBs could exhibit a punctate staining pattern that can be easily misinterpreted as RNA granules or even single RNA transcripts . Puncta were primarily detected in the nucleus as expected, since highly-PS-modified oligodeoxyribonucleotides (ODNs) are widely reported to bind nonspecifically to the nuclear matrix , , , , , .