Also, having 2-4 5.25" slots instead of 3.5" slots does not require that much extra space in the enclosure. And the noise reduction that can be achieved by mounting the HDDs in suspensions in those 5.25" slots is tremendous.
While you are right in terms of space, there is not much demand for 5.25 slots on mini itx enclosures, hell not even on micro and atx, we are moving away from optical drives, thus the main need of this slots. But in mini itx most want as small as possible and 5.25 slots are just too big for this purpose, and main reason you dont see them.
A case that you should look into is LIAN LI PC-Q25B
(atm there is a sale $20 off until 9/26), while it doesnt have any 5.25 slots, its small, fits a standard atx psu and a mini itx motherboard, whats good about it its that had a good space for hdds, given that by default its for rails, i think with some modding suspend 2 or more hdds.
Slightly bigger there is also the option of the LIAN LI PC-Q08B
similar to the Q25, but it has a 5.25 slot, but if you get a 140mm PSU (like Seasonic G360) there is enough room (my guess) to suspend hdds with some modding like adding some rails. Here is a pic for you to get some idea if you think is feasible,
Another case for mini itx that might also adapt with some modding and its cheap so might be worth a shot to see if you can builld what you want is APEX MI-008
, was reviewed by SPCR Apex MI-008: A Cheap Quiet mini-ITX Case?
, while it uses a form factor PSU, SPCR find it decent, but in time if it you dont find it good enough you could move into picoPSU-160-XT + 192W Adapter Power Kit
(or lesser unit depending on the build). There is an interesting thread that he suspends one hdd on it, AM2 mini-ITX Linux server
Maybe with some modding you could suspend another (maybe two, but i doubt it).