The curse of knowledge is what Lars refers to as the double-edged sword of having learned how to create and edit a podcast.
As Lars has explained on air, medical professionals will occasionally note that they know "too much" about how the human body works, and about how it gets sick.
He likens this as a broad analogy to the fact that he now has an ear for what makes for good audio (and what it sounds like). The latter is good for the show, but he notes that the inverse is true; he now also has an ear for what makes for bad audio.
This leads to a source of growing frustration over time. For starters, it makes small audio issues on the show seem like a much bigger deal than they will be for the average listener. Also, he says he can't stop noticing all the loopholes and phoned-in audio on popular media anymore, noting that they are "everywhere". This is the "curse" of knowledge.
In order to mitigate potential problems, the hosts have an extensive checklist that they walk their guests through point-by-point before any and all recordings.