I actually have an idea of how to do it. If say there was to ever be a reboot, have it set about 6 months into Spidey's career.
Spider-Man is a pop culture phenomenon. Video games, comics, merchandising, and an indevelopment film that's being shot on location, supervised and executive produced by Spider-Man himself. You could throw in a joke where Spidey completely makes up a whole new backstory for how he got his powers and what he really looks like underneath the mask.
Quentin Beck is the sfx supervisor on the film, a master of practical and visual effects, but due to the modern use of CGI, Beck's had trouble becoming contracted. This is sort of his last chance to prove what he's capable of and spark interest for his talents.
One day when Spidey is on set, the director shows him to one of Beck's effects, to which Spider-Man makes a passing comment on its' lack of believability. The director takes notice of this and asks to have Beck fired, to which Beck of course pleads to keep the position. Beck is offered a rather small sum of money to leave quietly, to which he refuses. Once fired/replaced, Beck swears vengence against Spidey for ruining his chance to become possibly renowned within the world of sfx.
It's pretty basic, but I think it would be cool in sort of a meta way. And later have Beck, as Myserio, somehow find out Spidey's true identity, to which he uses some sort of simulator or "funhouse" (sort like SM2 the game) that shows Spider-Man's greatest fears and his worst experiences. Could also be an interesting way to show what he has gone through up to this point (possibly having already experienced the death of Gwen).