The main villain could be a rogue demon teacher. He used to be a respected faculty member but was corrupted by dark powers. He now wants to use the students' powers for his own evil purposes, like opening a portal to a demon realm to bring in more powerful demons to rule the world.
Maybe it's a powerful and jealous student. This student has always been in the shadow of the more popular and talented students. So, he decides to use his knowledge of dark magic to create chaos in the school. He starts by turning students against each other and then plans to take over the school and use it as a base to spread his influence.
It could be an ancient demon that has been sealed beneath the Naruto Demon High School for centuries. Due to some recent events, like an earthquake or a powerful spell gone wrong, the seal is weakened and the demon starts to influence the students' minds. It wants to break free completely and destroy the school and everyone in it to regain its full power.
The main villain could be an ice demon with the power to manipulate time. It freezes entire villages in different time loops, causing chaos. Naruto and the demon slayers must figure out how to break the time - frozen spells and defeat this powerful demon. The demon could also have the ability to create illusions, making it even harder for the heroes to fight it.
In this kind of fanfiction, Gaara could start as an antagonist. He's the new kid from another school who transfers in. He has a very cold and intimidating demeanor. He gets into fights with Naruto and his friends because he has his own ideas about how things should be in the school. He doesn't trust easily and thinks everyone is out to get him. But as the story progresses, he could turn into an ally. Also, Danzo could be an antagonist. He's a strict, old - fashioned teacher who doesn't like Naruto's unruly behavior and tries to expel him from school at every chance he gets.
One possible main villain could be Mysterio. He could use his illusions to create chaos in the superhero high school and try to frame Peter Parker for it. Kingpin could also be a good choice. He might see the superhero high school as a threat to his criminal empire and try to take it down. And then there's Electro, who could be causing power outages in the school and endangering everyone.
A great plot might involve a school competition in the Naruto Demon High School. The main characters form a team and have to compete in various challenges that test their ninja and demon skills. Along the way, there are rivalries with other teams, and secrets about the school's history start to surface. Maybe the competition was actually set up by a hidden enemy to find the strongest students for some evil plan.
It could be Orochimaru. He's always interested in new forms of power and experimentation. He might see Wolverine as an interesting specimen to study and try to extract his healing factor or adamantium for his own purposes. This would put him in direct conflict with both Wolverine and Naruto, who would naturally oppose Orochimaru's evil plans.
Danzo could be a great main villain in a Naruto Frankenstein fanfiction. He's always been power - hungry and secretive. He might use the concept of creating a Frankenstein - like being to gain more power for Konoha in his own twisted way, but really it's all about his own control. He could be using parts of dead ninja's abilities or something like that, and Naruto would have to stop him.
Orochimaru could be a likely main villain. He has always been interested in Naruto's power and body. Maybe he finally devises a plan to kidnap Naruto and use his body for his own reincarnation experiments.
It could be Orochimaru. He might be interested in stealing the exosuit to enhance his own powers and immortality research. He could see the exosuit as a new way to achieve physical enhancements beyond what his current jutsu can do.
Another possibility is that the main villain could be a spirit or entity that has been trapped for centuries. It uses its influence to make the Hidden Leaf Village conduct 'experiment 101' on Naruto. The spirit hopes to use Naruto's body as a vessel to be reborn into the world and wreak havoc. So it manipulates the events and people involved in the experiment from the shadows.
Tenten could be a main female character. She could be the sporty girl in high school who challenges Naruto to various athletic competitions and during that time, starts to develop feelings for him. Ino could also be part of the harem, as the fashionable and sassy girl who tries to win Naruto over with her charm and style.