NgAgo uses 5' phosphorylated DNA guides as opposed to the RNA guides used by similar CRISPR-based genome editing technologies. These DNA guides must be directly delivered to the cells of interest and cannot be made from a plasmid like RNA guides can. Any inefficiencies in delivery of these DNA guides will likely lead to lower editing efficiency;

NgAgo is "one-guide-faithful" and can only load a guide DNA as the NgAgo protein is being produced. This means that, if NgAgo protein is translated but there is no guide DNA around for it to load, it will remain unloaded and will not be directed to cleave a target. To mitigate this issue and generate more successfully loaded NgAgo proteins, Gao et. al., 2016  suggest transfecting target cells with guide DNAs multiple times during the course of a single experiment;

Gao et. al., 2016 only demonstrated genome editing in a few mammalian cancer cell lines. Should researchers attempt to use NgAgo in other systems, there may be more optimization required than that documented in the paper;

Because CRISPR has had much longer to develop as a genome editing technology, there are many more resources available to scientists who would like to develop/use gRNAs and delivery systems for their organism of interest. There isn't yet a large amount of data on the best ways to design and deliver guide DNAs for NgAgo.