Marinette could be a main character even in this type of fanfiction. If a kwami becomes human, Marinette could be the one to help them adjust to the human world, given her own experiences with the miraculous and the kwamis.
The kwami Tikki could be the main character if she becomes human. She has a deep understanding of Marinette and the world of the miraculous. As a human, she could explore the world in a new way, make new friends, and perhaps even have adventures outside of just helping Marinette as a kwami.
Perhaps a kwami becomes human and tries to use their new form to protect their chosen holder in a more direct way. But they soon realize that being human also means having human weaknesses and they have to be careful not to expose their true identity. They could start to understand the human emotions of fear and vulnerability more deeply.
One main character could be an android named Kara, but instead of being a caretaker for a human child, she could be a powerful android leader. She might be the one making decisions about how humans are treated in the new reversed world. Another could be Markus, now a human rebel trying to fight against the android regime.
The kwamis themselves are also very much affected. Tikki and Plagg, for example. They have to adapt to new holders. They might have different ways of communicating and guiding their new heroes. Their own little 'kwami - world' is disrupted too. And other characters like Alya and Nino might also notice the changes in Marinette and Adrien and get involved in the story in different ways.
It could be a newly created android with unique abilities. Maybe an android with the power to sense the emotions of other androids from a distance.
A single adventurer could be the main character. This person might be a thrill - seeker who built a shrinking device and decided to explore the human body. Along the way, they make friends with some helpful bacteria and together they face the challenges of the body's inner environment.
Well, Lady could be a young artist named Elizabeth who is always looking for inspiration. And Tramp could be a vagabond musician named Jack. They would meet in the city's art district where Elizabeth is sketching and Jack is playing his guitar on the street corner.
Spyro and a scientist could be the main characters. The scientist is studying the strange phenomena that seem to connect the dragon world and the human world. Spyro stumbles upon the scientist's research site and they end up having to rely on each other. The scientist could learn a lot about Spyro's world through Spyro, and Spyro could learn about human intelligence and technology from the scientist.
The powerful human would be the central character. They might be an older, wiser human who has been sent to Equestria for a specific mission. Then there could be Pinkie Pie, who would befriend the human right away and introduce them to the joys and quirks of Equestria. And there could also be a villain, like Discord, who sees the powerful human as a new plaything or a threat to his chaos - filled world and tries to either befriend or destroy the human.
Obviously, Cortana in her human form would be the main character. But there could also be a scientist who was involved in the process of her becoming human, either intentionally or accidentally. This scientist could be a mentor or a conflict source for Cortana as she adjusts to her new life. Another possible main character could be a human friend that Cortana makes early on in her human existence, someone who helps her understand human culture and values.
A scientist could be a main character. They might use their intelligence to figure out the enemy's weaknesses and develop new weapons or strategies for the human strike back.