Setting: Far Future Space. Need all those uncharted worlds, that vast area to explore, the range of weirdness you can fit into the setting.
Open world (well galaxy) is a must, with dynamic sidequests, like local feuds amongst colony and established world nobility, titles to be claimed by force or by politics, alien invasions to fight off or aid, lost treasures (of the monetary or familial variety), strange space gods to deal with, just a big, living galaxy where stuff is always happening. So the Radiant thing Bethesda's been doing, but at it's full stated potential.
The main plot can be any old thing. Let's be honest, the main quest in any really open world RPG is just a thing you do when you've run out of other things to do. But I'd prefer a three-way civil war between federalist, who want the galaxy loosely governed by a weak central government whose only job is to try and limit the casualties from internal wars and to broker peaces when things get out of hand, with an enormous amount of autonomy for the individual worlds; an Imperial faction that wants a strong, elective monarchy, basically the Holy Roman Empire in space, and also closer to what it was suppose to be than it was historically;, and an Techno fetishist group that wants to use the galaxy's computers and nano-factories to convert the meatbags into a cybernetic hivemind, via forced implants and mass distribution of AI programs. And of course, a decent number of neutral worlds that want to keep the status quo, free-for-all style lack of government the galaxy was in at the start, that you can convert to one of the factions or help build into a fourth faction.
Gameplay wise, I like fallout's stats + perks system since it allows for a lot of customization, so I'd probably just expand that with a higher level cap. What I'd like to add is a bigger emphasis on diplomatic intrigues; forming alliances and negotiating or making small scale coups to accomplish goals as opposed to all murder with the occasional dialogue tree. I'd like NPCs that keep fairly detailed track of your behaviors and actions and factor those in when decided if and how much they want to help you, with a reach mechanic to determine where, how much, and in what ways a given NPC can help.
For example, a powerful warlord in a poor part of space could exert a lot of military and even diplomatic (in the form of implied force) weight in her part of the galaxy, but because she's fairly poor overall and has a bad reputation amongst the more civilized planet's gentry, she couldn't really force project against someone on the other side of the galaxy (logistical issues), and being close to her could hurt your chances for alliances in the core worlds, since the taint of blood soaked barbarism would make openly associating with you hurt a noble/plutocrat/politician's image amongst their fellows.
As I mentioned, the gameplay would be waited more towards politicking than kill all the bad guys. Even the combat would simply be a way to improve your standing or eliminate a rival from the field, an option rather than a requirement. Combat itself would probably be skyrim/new vegasy, with a emphasis on variety, with stealth, range attacks, and brute force being options.
Summary: A big open-world space game where the point is to start as some random asshole, and through negotiation, assassination, or just kicking, forge enough alliances to become a player in galactic level politics and determine the outcome of the biggest war to the stars, with an emphasis on alliance building, realpolitik, and manipulation of factions over slay the dragons, save the world.