So, it's a few years after the end of the first movie. Megamind is starting to feel the same burnout Metroman felt.
Roxanne and Minion are trying to be supportive, but they don't really know how to help.
He's also moving into a more "heroic" lair, and is trying out more heroic suits. (White and blue instead of black and blue.)
Anyways, the container that held the powers given to Titan is being transported, admittedly not very carefully, when it breaks, releasing the powers into the city and granting other people powers.
Now, the powers had been harvested from Metroman's DNA. The thing about DNA is that it degrades over time. So, a few years prior it would have given people exact copies of Metroman's powers, it doesn't do that this time.
There are gaps in the DNA that's granting powers, and the recipient's DNA fills in the gaps, altering the powers they're granted.
This also means it'll be harder to remove them.
There will be a scene where Megamind and Minion need help, and Metroman shows up to save them.
Obviously, people are at first elated that Metroman is alive, but then react angrily at realizing he just left them.
Roxanne will give a great speech about how the public never cared about Megamind or Metroman, and they should be ashamed of themselves for it.
There will also be a few characters who want to be heroes, but are granted powers that are seemingly useless. Eventually, they realize their powers are more than that, they are more than that, and figure out all that their powers are capable of.
Metroman tells Megamind that he doesn't need a "heroic" lair or costume, that he's a better hero as himself than when he's trying to be like Metroman.
They defeat a big bad who'd been rallying up superpowered criminals for a big fight.
The final scene shows that the new lair has design elements from Megamind and Metroman. It would also show that they have more people with powers to track down and potentially fight.
The new team is called Megamind and the Metro Men.
And it could lead into a TV series if necessary.