> I just wonder if the USB protocol can be hardened for this using some appropriate internal cabling

Honestly no idea. Should be doable but with personal computing being attacked every year, I would not hold my breath.

> Once you get to uATX and larger, this could potentially be via a PCIe adapter card too, right?

Sure, but then you have to budget your PCIe lanes. And once you get to a certain scale (a very small one in fact) then you have to consider getting a Threadripper board + CPU, and that increases the expense anywhere from 3x to 8x.

I thought about it lately and honestly it's either a Threadripper workstation with all the huge expenses that entails, or I'd probably just settle for an ITX form factor, cram it with 2-3 huge NVMe SSDs (8TB each), have a really good GPU and quiet cooling... and just expand horizontally if I ever need anything else (and make VERY sure it has at least two USB 4 / Thunderbolt ports that don't gimp the bandwidth to your SSDs or GPU so the expansion would be at 100% capacity).

Meaning that going for a classic PC does not makes sense if you want an internally expandable workstation. What's the point in a consumer board + a Ryzen 9950X and a big normal PC case if I can't put more than two old-school HDDs in there? Just to have a better airflow? Meh. I can put 2-3 Noctua coolers in an ITX case and it might even be quieter.