we run multiple instances for certain clients specifically due to the ESP limitation. In order to get around this we have setup some amazing stuff using n8n.io where data is passed through to different instances depending on actions like non/opens no/clicks, page hits etc… and then automatically added to different segments, Basically a monster operation running
Yes, you can have multiple sending domains, there is a plugin for that.
But in general I would go with @mikew 's suggestion.
One more thing: with just a little coding you can also do automatic imports / export between instances using the custom import bundle plugin. It makes sense if you seal with 10k+ data at the time, since the custom import runs in 2 min, with webhooks would take more then 50x.