I don't like the idea of making the cast all toads. It's good to make new connections like that, but it's even more important to harbor and develop the ones that already exist. Mario, Luigi, Princess, et al should be in the game--it just happens that Toad is the character you control.
It would be a great opportunity to show the inside of the castle... I've always wanted to explore the castle. Other games have always used it as a sort of backdrop for the real action--like Mario 64 with the plain, generic rooms--but Toad's life practically is the castle. You could have a whole game taking place in that huge castle... with maybe the courtyard and a little greenery out front.
As for the premise, that's never been the focus of Mario games, so that shouldn't get in our way. I'll go with this: Mario & Friends leave the castle--say, on a picnic. While gone, Toad must look after everything. He's also sort of the "in charge" guy, who all the other castle guards look to for guidance.
Even without Peach and the Bros., the castle should be full of life. So, I'll put a dungeon on the bottom floor--full of all the bad guys you wouldn't expect to be hanging around otherwise. Meanwhile, there are some lurkers--say, shy guys or boos--and there are pet chain chomps or wigglers scattered here and there. Plus, you've got the legions of castle guards and maybe a few travellers or guests.
Anyway, at some point, a conflict arises... I'm gonna go with castle siege. But it's not an ordinary Bowser-in-the-copter siege: No, this one's different. I don't know who should be in charge--maybe an uprising from the dungeon, perhaps--but the goal of the siege is simply to make a mess of things. It'll be like when you were a kid, home alone with your brother or a friend: Someone made a big mess, and you need it clean before Mom & Dad come back. You need to erase everything back to the way it was--and catch the bad guys. That's the premise of this game.