There could be a new, powerful dark ninja who has his own twisted ideology. He believes that strong ninja families like Naruto and Sakura's are a threat to his vision of a chaotic ninja world. So he sets out to destroy their family and everything they stand for.
Maybe an old enemy of the Hidden Leaf Village resurfaces. This enemy sees Naruto and Sakura's family as a symbol of the village's strength and hopes to break them apart to weaken the village. They might target their child first to get to Naruto and Sakura.
It could be a rogue ninja who is jealous of Naruto and Sakura's happy family. This ninja might have some grudge against Naruto from the past, and now that Naruto has a family, he wants to disrupt their peace.
It could be a rogue ninja who has a vendetta against Naruto and decides to target his son. Maybe this villain was once defeated by Naruto and now wants to take revenge by harming his family.
It could be a jealous relative who wants Naruto out of the picture so they can have more attention or power within the family.
The main villain could be a big, mean cat from the neighborhood. This cat is always trying to steal Sakura and Akatsuki's food and toys. It's territorial and doesn't like the two little kittens around. It chases them away from their favorite spots to sunbathe and play.
One possible plot could be that Naruto and Sakura face challenges in raising their child. Maybe their child has a special power that attracts the wrong kind of attention from villains in the ninja world. They have to teach their child how to control this power while also protecting their family from threats.
It could be a rogue ninja who has a vendetta against Naruto and wants to target his family. Maybe this ninja was once defeated by Naruto and now wants to take revenge by harming his loved ones, especially his and Sakura's child.
The main characters would obviously be Naruto and Sakura as they form the family. Their children would also be important characters, each with their own unique personalities and abilities.
It could be Orochimaru. He might be interested in Sakura's potential as a medic - ninja and wants to use her for his experiments. Naruto would then have to face Orochimaru once again to rescue Sakura and bring her home.
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.