Perhaps an old enemy has returned, stronger than ever. They might have been plotting during Naruto's sealing and now are ready to take on Naruto and the Hidden Leaf Village. This could be someone like Orochimaru who found a new way to gain power in Naruto's absence.
It could be an evil wizard from Negima's world who wants to use Naruto's power for his own dark purposes. This wizard might be aware of Naruto's unique sealing abilities and see it as a way to gain ultimate power over both the ninja and magical worlds.
It could be Orochimaru. He has always been interested in power and Naruto's unique abilities. With Naruto sealed away, Orochimaru might see it as a chance to steal whatever power Naruto had or use his absence to further his own evil plans in the ninja world.
A corrupt leader from a political - based crossover world might be the main antagonist. He views Naruto as a threat to his power, especially with the mystery of his seal. So, he tries to either keep Naruto sealed away permanently or use the situation to gain more control over his own people by creating fear around Naruto's presence in their world.
The main antagonist could be a new character created specifically for the fanfiction. This character might be from a long - lost clan that has a grudge against the Uzumaki clan, of which Naruto is a part. Since Naruto is the last of the Uzumaki in the village, sealing him away would be their first step in getting revenge on the clan, and they would do everything in their power to keep him sealed.
Maybe it's an ancient evil that was sealed away long before Naruto but managed to break free during his 1000 - year imprisonment. This evil entity now wants to destroy the world and sees Naruto as an obstacle once he is unsealed.
Naruto is surely one of the main characters since he is the one being sealed. His friends like Sasuke, Sakura, and Kakashi might also be main characters as they would likely be involved in the events related to Naruto's sealing.
Another possibility is a character who has been corrupted by the same power that was used to seal Naruto. This character could see Naruto's awakening as a threat to their new - found power or status. For example, if the sealing was related to some ancient and dark chakra, a ninja who has been influenced by this chakra might oppose Naruto.
Maybe the village has changed a great deal while Naruto was sealed. When he finally breaks free, he has to face a whole new set of challenges and enemies that have emerged in his absence. There could be new political situations in the Hidden Leaf Village as well.
It could be an ancient evil ninja who was sealed away long ago and somehow gets released in the time chamber. Naruto has to face this powerful foe while also dealing with the time - warped environment of the chamber.
Obviously, Naruto is one of the main characters since he is the one sealed in time. His friends like Sasuke, Sakura, and Kakashi are likely to be main characters too as they would be involved in trying to save him.