Honestly, even though I think long time fans would hate the idea, but I would lose the main characters and create new characters. The game would be platform/shooter based similar to Uncharted. But it would be about a normal family who got caught up in the outbreak and the evacuation from their city. The game would follow their escape from their home, to where ever they end up.
I think I realize that going back to pre-rendered graphics wouldn't work. But I would want to ditch the RE4/5/6 style. The only choice is a free roaming 3rd person game similar to Uncharted, Tomb Raider and Grand Theft Auto IV.
My good movie of the week: "Coraline" Game of the month: Heavy Rain (PS3)
Give it the traditional gameplay with the option to switch it to over-the-shoulder at will. It would be a large trapped environment that you have to play detective in solving puzzles and such to find new paths and items in the backtracking that you do. Ammo and health would not be dropped by enemies and you'd have to find it lying around. Also lots of notes.
Before you die you see the Tails Doll---Backdrop Observer of the Metroid: Other M board Apparently Edward: Wise Old Sage of Korodai