I live in the Baltimore area and make a regular run to Western South Carolina. I always take 81 to Winchester, then 7=>340=>70 East. You can also stay on 81 to Hagerstown and pick up 70 there. It's further, but weekend traffic through Harpers Ferry can be frustrating. Stay off of 95 if you possibly can. Hotels: For Baltimore, consider staying in Hunt Valley. You can take the light rail downtown, and if you're feeling adventurous (or just hate driving around DC) you could take a train to Washington. I have no suggestions for DC hotels. The only time I stay overnight in the area is on my employers dime, and it's insanely expensive.
Bonus: If you are in Hunt Valley on a Saturday morning, there is a really good Cars & Coffee that starts around sunrise a runs until mid-morning.