Hrm. I might stick with Unity and go with the prefab method (at least for now). MonoGame sounds great, but I am not too keen on establishing my own physics engine, my own 3D rendering, etc. While I indeed plan on using Spriter for my project, the goal is to have an engine like this (Don't Starve Together).
It actually uses Spriter for it's animations as well, only in a 3D world. The terrain is a flat quad that renders via tiles, all entities are 2D Spriter models, and there is a form of physics for items. In addition, it utilizes Lua for content scripting. I really feel an engine like this has a ton of promise, however, rather than modding it...I'd like to create my own rendition. On reason is because some things have been hardcoded into the core engine and not exposed to scripting. Another is purely the challenge of getting such an engine working.
So Unity might work best for me. I know I could definitely achieve all of these goals via MonoGame, however, I'm a designer more than I am a developer. I enjoy the art and system design far more than I do implementing said engine. As such I feel like trying to learn how to get all these working in MonoGame may cause me to give up from frustration if I cannot achieve my aims at a reasonable pace.
I'll look into MonoGame a bit though, maybe it is easier than I am expecting. If you happen to have some specifics I should look into, please share them.