When I was playing MUA 2 I always got very frustrated by the stupid Nanite controlled mini-villains and leaders. The combination of the sheer masses of Nanite controlled citizens and the fact that the only reason they had powers was a few big ones being around was incredibly angering. They would crowd you and slowly kill your friends while the leaders shot you from afar, and if you didn't destroy the teleporters, the leaders would respawn before you could clear the area.
I wish I could say a boss though, because though the Nanite People were frustrating, Titanium Man made me want to Falco Punch my TV.