I say make 4 a lesson of him now being more resilent and less "green" as he was in the first two (and in the third it looks like he is getting his crap together but is becoming too arrogant and gets sidetracked with revenge) and in 4 he now has to save a villain instead of giving up on them (like he did for Norman and Otto). Enter Curt Conners, who has a wife and kids, like what Pete and MJ has.
He sees the strain that being "super-powered" can be and how it may ruin a family, even with good intentions. He must protect him from the police, himself and Kraven the Hunter, who is in town trying to kill him as a trophy. Give Kraven a new AND DEEPER backstory (like Sandman). And the Lizard is a dangerous monster that Pete must use his scientific know-how to save. At the same time Kraven is now hunting him and it becomes cat and mouse (before the climax it would be amazing if he got a dramatic buried alive sequence similar to Kill Bill Vol. 2 but straight out of Kraven's Last Hunt).
Have it end dark with Pete having given hope on Conners but after Aunt May dies, revealing she knew all along, he realizes he is a good man and just not for Uncle Ben, but for himself he cannot give up on Conners like he did on Norman, Otto and his failure to save Harry due to his own selfishness.
In the end Kraven kills himself after he is defeated (changing it a little) by the Spider and thinks he killed the Lizard. Spidey saves Conners and everything is okay.
Then for 5 I'd bring back the symbiote and perhaps it melds with a sociopath named Kassidy (I know they are different symbiotes in the comics but hey, you have to condense for movies)?
But after 4 it will get even harder to keep it on Peter's inner-struggles and he and MJ trying to make things work. In fact by 5, and especially 6, I could see them being forced to face the ultimatum of the comics that he either continues to grow (starts trying/does become a father) or remain in the boring status quo (what has been killing the comics for the last 10 years or so).
I think 4 or 5 would be good. 6 may be pushing it before it becomes Bond-ish and too episodic, I'm afraid though.