Sure
This room is a mess. - ok
This room is in a mess. ok
Basically the same thing.
I don't think there is any distinction for me in most cases.
If the room were empty & decorated badly, then I'd be more inclined to say "is a mess", as "in a mess" suggests the arrangement of things being messy.
But, that said, "is a mess" does work for the things in a room too. So the exclusion only applies one way round.
Empty ugly room - "is a mess"
full messy room - either one.