For something sorta new I'd say Spelljammer. NOT to connect other settings with, or indeed have a FREAKIN' thing to do with any other setting, but to exist as an isolated new setting all of it's own. I don't want to play Spelljammer to play Forgotten Realms, or Dragonlance, or Greyhawk, etc. I want to play Spelljammer to PLAY SPELLJAMMER.
I've always wanted to do a Spelljammer thing that was more akin to regular Sci-Fi/Space Opera, in a way. It would involve the following:
Each planet with intelligent life on it would only have a tiny number of sentient species, or even just one. There could be hints that these species were spread out by a Precursor race or something, which is why you might find dragons or elves on different worlds. Like in most SF, most of these people aren't spelljamming-capable, leading those who are sometimes fighting over what to do with "groundlings." Many of the spelljamming people have numerous colony worlds. Spacefaring races have formed federations and alliances, of course--but based on worlds and spheres, not necessarily races, leading to conflict between members of the same species.
The outer and inner planes wouldn't really be a thing. Fiends and celestials could
be some of those Precursor races, with (as one possibility) celestials being rare individuals scattered about and fiends gathering on Hellworlds, from which they occasionally strike out like Firefly's reavers. Other things like modrons or slaad would just be rather weird intelligent species. As a side effect, the gods would be distant and you couldn't planeshift to meet them. Additionally, each world would have its own Feywild and Shadowfell (if those places were included in this setting). Some worlds have a heavy presence of one or the other, leading to fruitful garden worlds and desolate shadow worlds.
Elementals would be just strange forms of life found on other worlds. Rocky and otherwise lifeless and/or airless worlds would be filled with earth elementals; water worlds would have water elementals; gas giants would have air elementals; stars would have fire elementals.
There would be wormholes--possibly with actual worms in them, because it's D&D--that might connect some crystal spheres, allowing for another way of travel.