You see this to some extent in Oblivion, but, at higher levels, I can run faster than most of the horses anyway... and I can't fight from horseback (yet), so, I just don't bother with them.
In a vehicle, most critters would run when they heard you anyway. Death Claws, and possibly Cazadores could be a problem though..... A Death claw could probably open up the cab of a truck like a can of sardines... with much the same result. The contents thereof get eaten. Cazadores would just come in thru the window. (Roll it up?) Most small arms would be able to penetrate the body work, and you would definitely have to do something about their propensity to explode.... that would play hell with whatever inventory you had stashed on the vehicle.
I could see the driver being able to attack with one handed weapons, even possibly using vats.... two handed would either have to be a no-no, or, with SEVERE penalties to accuracy/spread. Being able to run over your opponent would be a requirement.
