Not only do the characters have their guns and whatnot... They have magic and powers.
So for setting, I'm thinking that the G.E.C.Ks were activated and the world was returned to its normal, green self.... But after 1000 or so years, China nuked them..: again.
Everyone went back into the vaults, and a lucky few decide to break out.
Hinge different from Fallout 3 would be:
Characters can use magic or other powers.
More radio stations.
A new Faction...
NetheronCorp: A Neutral Faction, their scientists can give you medications, or offer you money, but you must be experimented on. Their merchants will try to sell you weapons. And, if you're lucky... Their boss can give you missions. (Depends on karma alignment what meds, experiments, or missions you get.)
Edit: ignore the thumbs down>_<