I think a mod of this size would have to be done in increments, at least to do justice to cities of that size.
As to how to handle explaining why. The PC could be part of an expedition that is sent out to explore this route, a scout perhaps. You are given money, some trade goods, probably both a melee weapon and some sort of handgun or rifle and depending on the organization maybe a modified Pipboy or something similiar. The Pipboy would be a tracking device and a journal. Your orders might be to foster goodwill with people you find along the way, if possible. Maybe you carry a beacon or the Pipboy has one, that you use to signal the main body of the expedition when an area has been cleared.
A mod with two or three big ruined cities and a stretch of highway that includes a couple smaller areas would be an exciting prospect to me. I've only offered a possible good path just to test the waters.