For me, it’s that you can’t enable TRIM which can slow writes if the drive is close to full. Running from a USB 3 external has a few issues.

Virtual instruments are best housed internally if you have room, but you should be able to have VI data libraries on a fast external SSD as well if you run out of internal space. I'd suggest a HD for longer-term storage and a second for Time Machine. You can certainly offload old DP Projects to an external drive, but if you do so, you should have two external drives, with one of the two backing everything up with Time Machine. These drives have been selling for close to $200 as of late. I use BackBlaze (cloud) plus externals (local) if you are a Costco member, they are having a very nice sale on Seagate 8TB external drives (with USB3 hub built in). if you don't have at least two copies of your data, you are living a fraught life.

I'd recommend you also get a large backup drive and keep Time Machine rolling at all time. SATA will slow things down considerably if you go that route. You can roll your own using enclosures that are available as well.

Thunderbolt will be the fastest, but you may not need that level of performance, especially with audio. I'm sure Mike will weigh in here, but my experience has been good with USB3, which generally involves less expensive hardware, i.e. I also may want to purchase & install a couple more virtual instruments (probably acoustic guitar + orchestral strings) and I assume they will perform best if installed on the internal drive. Second question: Once I start using the external SSD, should I move some completed DP projects from the internal drive to the external drive to make more room on the internal drive? I assume it's best to use the internal drive for each new current project. Any recommendations on an economical enclosure/drive for best performance? If I purchase an external drive to hook up to my Mac Mini, which type of connection will be fastest and best: USB 3, Firewire 400, or Thunderbolt 1? My Motu 828 can hook up via Firewire or USB, so I have some flexibilty. I've done that previously on my mid-2012 MacBook Pro, but on OWC's site the instructions for the Mac mini are a lot more complex. I'm running out of space on my mid-2012 mac mini and I'm not sure I want to tear it open to replace the SSD with a larger one.

Mac mini external hard drive