Its possible for him to main event Mania 21, but I dont think it will happen if he stays on Smackdown. The way I see it, this year Smackdown will headline Mania with Eddie on top either defending the title, or more likely winning it for the second time. Not sure who he will face at this point, but I would say with it being in LA they will put on Eddie on top.
If Cena were to do a heel turn he could possibly take the title from Eddie and then defend at Mania against him, but I dont see that. More likely is that Cena will be put in another match (wouldn't be the worst idea to do Rock-Cena next year to really establish Cena as a main eventer).
The way I see it, the top matches for Mania 21 if I were to guess right now would be:
Eddie vs ???? (maybe Brock will be back by then) WWE Title
Orton vs HHH World Title
Goldberg vs Austin
Cena vs Rock
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