I use a 203 degree thermostat. It's the only engine mod I've ever found to work on my diesel truck.
If you want to go E85 (non-diesel), modify your engine to take advantage of its very high octane. 14:1 compression and a huge ignition advance are possible. Both improve engine efficiency. Keep in mind that E85 has only 60% the heating value of gasoline, so you will have to accommodate a bigger fuel flow.
An idea I recently heard, but have not (obviously) tried but may be good for this project: Motorcycle tires. There are 16" motorcycle tires available (they are used on Gold Wings) and their small contact patch may afford lower rolling resistance. I have not tried this myself, so you are on your own. Motorcycle tires are considerably softer than car tires and wear quickly.
2000 Ford F-350 Super Cab Pickup
4x2, 6 speed manual
Regeared to 3.08:1
4 inch suspension slam
Aero mods: "Fastback" fairing and rugged air dam and side skirts
Stock MPG: 19
Summer MPG: 27.0
Winter MPG: 24