With the -sk keys, you no longer need to install any software (gnupg, pinentry, yubikey CLI etc.), or run gpg-agent which has always had reliability issues etc. It should all Just Work out of the box now. GitHub was the last piece of the puzzle for us, and for example I can now change our team's onboarding docs from "follow this long OS specific guide to setup SSH w/ gnupg and ykman" to "run ssh-keygen -t ed25519-sk".
There's some confusion in this thread, but you can use ssh-keygen to generate either a public and private key pair, with the private file being a stub and the validation still happening on your physical YubiKey, OR you can omit the private key stub entirely with "-O resident" option to ssh-keygen allowing you to add your key to your ssh agent on any machine you plug it in (for good and bad).