The highly labeled DNA nanoballs provide small, highly-charged, yet extremely bright fluorescent sources from which to detect binding events with millisecond exposures and high signal-to-noise ratios. Similarly designed DNA nanostructures are also currently being used in other next-generation sequencing endeavors.5 Using these bright DNA nanostructures, we investigated a modified form of sequencing by synthesis, in which it is necessary to detect the addition of a nucleotide as it is incorporated in real-time into the growing DNA strand.