Kaguya could be an interesting choice. She is extremely powerful and has a complex backstory. Her motives were initially self - serving and evil. If she were somehow resurrected or a situation where Naruto had to interact with her in a different time - line, it could make for a great fanfiction. Naruto's ideology of peace and friendship could clash and then potentially influence her.
It could be a new ice - using ninja who has a grudge against Naruto. Maybe this ninja wants to prove himself as the most powerful ice user and sees Naruto as a threat, so he freezes Naruto in ice.
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 Ino's unique abilities, like her mind - control jutsu, for his own evil experiments. So he kidnaps her, and Naruto has to fight against Orochimaru's snake - like techniques to save Ino.
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 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.