I'd like to see someone run 5WR all game, with their WR's rotating in one position, and backups, running backs, and TE's rotating in all of the other positions.
Destroy the CB stuck defending them the entire game.
I did that for a quarter with a Dual Threat QB. Still have some kinks to work out, but I think I should be able to do some actual damage with it, while tiring the CBs.
Running can leave the secondary relatively unaffected though. Your front seven will be spent after the first half - which can help the passing game in the second half, but the running game will be helped even more.