the Chicago Enclave has alot of potential :3 not as a villain but consider this : what if the enclave changes their tactics and becomes one of the good sides in order to survive? what if they open their doors and let the wastelanders into their ranks? and become the true model of democracy, the very same model that the NCR is failing to achieve.
I'm a huge enclave fan so maybe I'm a bit biased towards this. But the enclave are simply just too cool to die off.
---- Imagine this scenario ----
You're a clone, created by the enclave to act as an "emissary" between the enclave and the wasteland communities around the city of Chicago (in NV it is hinted that the enclave has a base in Chicago) . This way the "customization" options are better immersed into the game, at start you see a lab with alot of lab rats studying a tank. and one by one the customization options appear. (sex, age, appearance, S.P.E.C.I.A.L, skills, perks)
The villain can be another conservative branch of the enclave which prefers to follow it's own ways. The Caesar's Legion can also be present there, dressed in thick fur clothes (because Chicago is colder). the setting can imitate the Roman invasion of Britain and north Europe, in which the Romans fought in a snowy climate.