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.
It could be Orochimaru. He's always been interested in obtaining power and immortality. The Blade of the Immortal would be a great addition to his collection of powerful items. He could try to steal it from Naruto if he knew Naruto had it.
It could be a rogue ninja who has somehow learned about Thea Queen's world and wants to conquer it using his ninja techniques. He might see it as a new land full of resources and weak opponents compared to the shinobi world.
A new character could be introduced as the main villain. For example, a powerful demon from another realm who has the Devil Trigger ability and wants to conquer Naruto's world. This demon could have minions with similar powers and Naruto would have to figure out their weaknesses in order to defeat them.
It could be Kabuto. Since he has a lot of knowledge about medical ninjutsu and experiments, he might see Naruto's robotic form as a threat or something he can use for his own evil purposes. He could try to control Naruto's robotic functions and turn him against his friends.
There could be a group of powerful out - of - world beings who are interested in the chakra of the Hokages. They revive the Hokages themselves, but with the intention of stealing their chakra. They are extremely powerful and have abilities that the ninja world has never seen before. Their arrival shakes the very foundation of the ninja world and forces the Hokages and Naruto to come up with new strategies to defeat them.