Well given Mysterio's skills with illusions etc he could pull of quite a few paranoid bizarre but nonetheless wonderful sequences for both Spidey & the citizens of NYC to perhaps try & make them go over the edge. I mean from ideas such as creating tidal waves, earthquakes, swarms of killer bees to perhaps clearing out the city by a fake asteroid coming towards Earth etc.
These are just ideas but I'm sure the filmmakers would have some interesting ideas in store for Mysterio vs Spidey. More of a psychological battle I'd say.
Another secondary foe like Shocker or Hammerhead in the mix again would probably be on the cards.