Far From Home Villain -
Loki (MCU)
This is the beauty of this thread. Technically, by the canon of the OP and all given replies, Doofenshmirtz has replaced Loki. This means that Loki is now completely original to the universe. I could definitely see Loki striking now. Some of Earth's greatest heroes are gone, and it's certainly a vulnerable place. We've never seen Spider-Man go toe-to-toe with someone as versatile as Loki, so I think this might end up being fairly interesting. And I would personally be intrigued to see how Peter's untrained Spider-Sense would work with real magic instead of technology. Loki has no issue impersonating Super Heroes, and revealing Peter's secret identity to the public wouldn't be far-fetched either. I think everything is still plausible in terms of Spider-Man being able to
hypothetically beat Loki (if all goes wrong, we still have Doctor Strange), and I think it could still set up well for No Way Home.