As many have touched on this post already, the main difference is price. But sometimes that price is minor. For an "average" NFL player, you may only pay $25-50 less for an issued jersey than a worn one. But if you collect that player (or in my case a University), it is well worth it.

Bigger name players are one way to go for the issued jersey, as say you may not want to shell out 12k for Ichiro, but might pay 3k for his issued jersey (I would not personally, but for instance...).

Also, game worn can carry a much deeper significance depending on how and when that player wore those jerseys, cleats, helmet, etc.

I think for framing and potentially getting them signed, game issued is the way to go. But if you are into the torn, grass stained, mud, stink and rips then game worn is for you.