1 word: Venom.
BUT don't kill him off as easy as Doc Ock or the Green Goblin, have him as an ongoing character that Spidey defeats at the end but does not kill...also tie in Green Goblin 2, so Spidey is spread out trying to stop them both.
I really want Venom to be portrayed as hugely powerful, ripping apart cars etc, give Spiderman a real foe to fight against.
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