Maybe in a new style way merge the lives of Browns/Griffins
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Twist: Lois is finally mayor and thusly needs to deal with the upkeep of her town while also dealing with the (Stan smith/dir. bullock) CIA who has had its eye on quahog for quite some time now after (secretly) learning of Stewies mad genius. Of course he is somewhat older now and has things under control; because he just gets smarter and is always three step ahead of anyone who dares interfere with his plans for world domination. Also Rupert is now a cyborg bear who is fully functional. Le catch? Rupert is only functional around stewie. Meg and Chris are in their later years of high school. Meg is still Meg........ Chris on the other hand has become a semi-popular linebacker (lol could that work?! Heh) he hangs with the popular kids, he's still dumb as rocks, and he's a jock but he's an outcast of his own kind: he's part of the in crowd but doesn't feel he belongs(depending on how fans receive this change to Chris' character, it's open for change).
anyway I don't want to run anyone's ears off but this is an idea of mine that I've actually put some thought into oddly enough.