I run a NAS on a USB 2.0 boot disk, and the only issue I have with it is that systemd-journald really isn't built with slow disks in mind. Doing a journalctl operation with 6 months of log files takes a good minute or two because of journalctl's non-optimal file access patterns.
Not questioning a great project, but just curiosity about this small aside: why is USB 2.0 not suitable for the OS?
On a NAS, is it doing anything other than boot-time reading, and maybe occasionally writing a little data?