First check if your drive uses GPT or MBR partition table. It should be MBR.
Theoretical every homebrew/app can run from usb drive, if it support it. E.g homebrew channel, USB Loader GX. In USB-Loader GX under settings "custom path" can be set to read the .dol from USB.
If you have also other custom channel installed e.g. emulator check them if they can run by using the .dol on usb. I dont know wich is able to do it or not. Do this to verify if its a homebrew channel only problem.
And please post a syscheck.