An anti - hero or a morally grey character might be the antagonist. This character could have a different view on relationships and superhero life. He convinces Spider Man that the harem is holding him back from achieving greater things. And Spider Man, being influenced, betrays the harem.
One possible plotline could be that Spider Man, perhaps due to some mind - control or misunderstanding, turns against the members of his harem. Maybe he starts working with a villain who convinces him that his relationships in the harem are a weakness. Another could be that he accidentally reveals secrets of the harem members, which they see as a betrayal.
It could be a new character, someone who is jealous of Naruto's growing power and popularity among the girls. This person might spread false information to turn everyone against Naruto. Maybe a rogue ninja who has infiltrated the village and has a vendetta against Naruto for some unknown reason.
Gwen Stacy is an obvious choice. In different universes, she has different relationships with Spider - Man. Another could be Mary Jane. She has always been an important part of Spider - Man's life. Black Cat might also be in the harem as she has a complex and flirtatious relationship with Spider - Man in the comics.
The Green Goblin could be a great main antagonist even in a Spider Man reborn story. Maybe in this version, he has developed a new form of insanity - inducing gas that affects Spider Man's new powers. Another possibility is Doctor Octopus. He could have found a way to merge his mechanical arms with some sort of alien technology, making him far more powerful and a real threat to Spider Man reborn.
It could be a corrupted version of an old ally. For example, a former S.H.I.E.L.D. agent who was exposed to some strange space radiation. This has turned him evil and he now wants to use his knowledge of Earth and his new - found space powers to create chaos. He blames Spider Man for not being able to save him from the radiation and is determined to make Spider Man pay, all while causing destruction across the galaxy.
Perhaps Doctor Octopus. But instead of just having mechanical arms, his mutation gives him the ability to control any metal object in the city. He wants to take over the city using his newfound powers and sees Spider - Man as the only obstacle.
A powerful alien being with a hunger for anything that moves could be the antagonist. It sees Spider - Man as just another morsel to devour. It has the ability to create portals to swallow its prey whole, and Spider - Man has to figure out how to close these portals and defeat the alien before he becomes a permanent part of its diet.
It could be one of the harem members who has a hidden dark side. Maybe she's jealous of Naruto's closeness to others in the harem and decides to turn the rest against him, so she becomes the main antagonist.
It could be the Green Goblin. In the sequel, he could return more powerful and with a new plan. Maybe he has found a way to enhance his strength and insanity using some new Oscorp technology. He could target Spider - Man not only for revenge but also to prove his superiority over the web - slinger.
The Green Goblin could be a great main antagonist. Imagine in this other world, he has even more advanced gliders and pumpkin bombs. He could be ruling over a part of the city with his goblin minions, and Spider Man has to stop him from spreading his reign of terror further. His maniacal laugh and unpredictable nature would make him a formidable foe in this new world.