Random enemy placment in the next RE4 style game would ramp up the replay value. It works for Left 4 Dead and it will also happen in the Wii version of The Grinder.
I think the ability to hide from Nemesis as in Silent Hill Shattered Memory and Metal Gear Solid would make for some tense moments too, like duck into a store room and peek through a keyhole or under the door.
Give it the same camera style as RE4&5. But add a fear meter, the more afraid the player becomes, the harder it is to aim and move, making headshots and such, much harder to make, which will help make the game much more tense.