Structured Mutants & Masterminds 3e
Around the F2F table we've used it for a sci-fi/future earth type game as well as a version of Star Wars.
The main thing is, I think, to think about concepts in a very mechanical fashion. Establish how, mechanically, certain similar things are done in the game. For instance, if the characters are "normal" characters relying on weapons of some sort, come up with some general guidelines for how those should be built, what minimums and maximums there are, etc.
Don't be afraid to have things slightly unbalanced. In most M&M games everyone builds to the point total, period.
If you're going for something that's going to be more focused or concept driven, assuming the group can handle it, it's ok if maybe things are not perfectly equal.
In the Star Wars game, for example, the person who chose to play a droid ended up not needing all the points. It was fine. Rather than stuffing bells and whistles on that weren't needed, they just were done, and the character did all the stuff the player wanted of them, and it was all good in the end.