Maybe an ancient evil spirit that has been awakened due to some mistake. It targets Ageha because she has a pure and powerful chakra. Naruto, being the hero he is, tries to fight the spirit, but he quickly realizes that he needs Ageha's help as well as the help of all his friends to defeat this powerful foe.
The main villain could be Darkseid. Imagine if he somehow finds a way to enter the Naruto universe. He would be a formidable foe for both Naruto and Supergirl. His omega beams and immense strength would be a huge challenge for them to overcome.
It could be a rogue ninja from the village with the Tenshikage. Maybe he's jealous of the Tenshikage's power and wants to take it for himself. He could be causing chaos in the village, stealing important ninja scrolls and attacking innocent villagers.
A new character could be introduced as the main villain. This character could be someone from an ancient clan that was once in control of the 10 - tailed beast but lost it. Now, seeing Naruto with that power, they want it back and will stop at nothing to get it. They could have unique powers and abilities that make them a formidable foe for Naruto and his friends.
It could be a new character, a powerful dark wizard who wants to use the combined power of Naruto's chakra and Pikachu's electricity for his own evil purposes. He creates all sorts of dark creatures and sends them after Naruto and Pikachu to try and capture them. He's very cunning and has a lot of minions to do his bidding.
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.