Orochimaru would be a great main villain. He's always been interested in power and secrets, so a secret base full of forbidden knowledge would be right up his alley. He could be trying to use the resources in the base to create even more powerful jutsu or to bring back the dead.
A new, original villain could be created. For example, a rogue ninja who was once part of a secret organization that built the base. He was betrayed and left for dead, but now he's back to claim the base and use its power to take revenge on the ninja world. He could have unique abilities and a deep understanding of the base's secrets, making him a formidable opponent for Naruto and the others.
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.
A powerful demon from another dimension could be the main villain. This demon has noticed Natsu's growing power and sees him as a threat. The demon has the ability to create illusions and false memories, which could be used to drive a wedge between Natsu and the Fairy Tail guild. He works in secret, slowly weakening Natsu's mental state before making a big move.
Maybe Orochimaru somehow gets his hands on a Black Lantern ring. He already has a thirst for power and immortality, and with the Black Lantern power, he could become an even more formidable and terrifying villain. He might use it to resurrect his past experiments and create an army of dark minions to take over Konoha.
It could be an unknown, ancient evil that has been awakened. This villain might have powers far beyond what Naruto and Sasuke have faced before. Maybe it's an entity from a forgotten era that was sealed away long ago and now has broken free.
Perhaps an evil Pokemon scientist who has created a device that can control the minds of Pokemon. He discovers Naruto's arrival and sees him as a threat. So, he teams up with some of the most powerful and aggressive Pokemon to stop Naruto. He has no regard for the well - being of Pokemon or the balance of the world, only his own ambition to rule.
A new character could be created as the main villain. Maybe a rogue ANBU agent who was once a friend of Naruto and Sasuke but has been corrupted by power. This character would know all the ins and outs of the ANBU, making it very difficult for Naruto and Sasuke to stop him as he tries to take over the ninja villages using the secrets he learned while in the ANBU.