One folder layout for every handheld
Every frontend has opinions about folder names. Some want megadrive, some want genesis, some want both. After the third reorganisation I picked one convention and stuck to it.
I follow the lowercase names used by most Linux handheld firmwares: snes, gba, psx, n64, dreamcast and so on. Frontends that disagree get a small mapping file instead of a renamed folder.
Artwork lives next to the games, scraped once on the desktop and copied everywhere. That alone saves an evening per device.
The rule that matters most: the desktop copy is the source of truth. Devices only ever receive files, they never send them back, except for saves.