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1. Give MJ an abusive mother.
This is just because the abusive FATHER angle has been so overused that it's practically a dead horse trope, not shocking or possessing any verisimilitude, it's almost been reduced to nothing more than a shorthand. Off the top of my head, Doctor Octopus and the Green Goblin have both had abusive fathers, and I'm sure that's just the tip of the iceberg in the Spider-Man mythos alone. And on the flipside, there are almost no abusive mothers anywhere in pop culture, so this felt like a change that would make things fresh and original without changing the underlying meaning of anything.
However, I did come up with a subplot involving MJ's abusive father being in pursuit of her, and a physical threat, in contrast to my idea of her mother simply being a psychological attacker in her clinical narcissism. So forget it.
2. Make the Chameleon the killer of Peter's parents.
Chameleon is a supervillain who's almost unworkable, since the disguise business really doesn't mesh well with Spidey's storytelling. He's kind of a joke, these days. The last thing I heard him doing in canon was proclaiming he was gay for Spider-Man and committing suicide (he got better), then getting handed an L by Aunt May, of all people. Now apparently he's got a gimmick where he boils people in acid when he impersonates them, and also he raped (but not really) Peter's roommate. Not the stuff of an A-lister.
Now, Peter's parents being spies in the first place is something to be massaged, since once you say "Peter's dad is James Bond," you're on thin ice. I figure they could just be one of those non-superspy secret agents, a handler or something, which is realistic enough. As long as Peter's place in the MU is that of a relative young'un, it makes sense for his parents to have a certain prominence. That Nick Fury or someone can say "I knew your father."
Still, that leaves Red Skull killing the 'rents, and Red Skull doing the deed makes it really more of a Captain America story than a Spider-Man story. So instead, why not make Chameleon some kind of spymaster mastermind? It keeps it in the family, so to speak, while also upping Chameleon's threat level.
And no, we're leaving Uncle Ben's death the act of a nameless burglar. Although...
3. Peter tells Uncle Ben he's Spider-Man.
It's an obvious move, since Ben dies anyway, but I figure the two should have one knockdown, drag-out talk about Peter being Spider-Man before Ben goes the way of all mentors. I figure for Ben's death to really land--and a high school Spider-Man should really still be feeling the sting of losing him--we should actually get to see Ben being a good father.