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.
The main villain could be a corrupted legendary Pokemon. It has been influenced by negative energy and wants to plunge the Pokemon world into chaos. When Naruto arrives, it sees him as an interesting target and tries to corrupt him as well. It uses its unique powers to create illusions and summon other Pokemon to do its bidding, making it a very difficult enemy to defeat.
Another antagonist could be a powerful and corrupted legendary Pokemon. It could be causing chaos in the Pokemon world and Naruto would have to use his skills and the power of his Pokemon team to stop it. This would be a great challenge as legendary Pokemon are extremely powerful, but Naruto has his own set of unique abilities that could give him an edge.
A new villain could be a powerful and dark psychic - type Pokemon. This Pokemon could have the ability to turn Ash into a Pokemon as part of its grand plan to take over the Pokemon world. It sees Ash, who has always been a symbol of hope and a strong trainer, as a threat even in his human form. So, by turning him into a Pokemon, it hopes to disrupt the balance and order that Ash has been a part of maintaining.
It could be a Pokemon itself. Maybe a dark - type Pokemon with a grudge against humans and Pikachu in particular. This Pokemon could be using its powers to cause chaos in the city, and Pikachu has to figure out its motives and stop it before it's too late.
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 new evil organization could be created for the fanfiction. They could be a group of scientists who want to use Pokemon for their own cruel experiments. Angie and Ash find out about their plans and have to stop them before they harm too many Pokemon. They might be led by a mysterious figure who has a personal vendetta against Ash for some reason.
A powerful and greedy Pokémon collector could be the main villain. He wants to capture all the rarest Pokémon for his own collection, regardless of the harm it does to the Pokémon and their habitats. Ash and Caroline would have to stop him from achieving his evil goals.