Having the nest mechanic make a comeback is probably the most efficient, logical idea of all.
I like to think bigger, but I've always been a dreamer:
When I was still in the industry I'd occasionally make the suggestion to have "intelligent" respawns in games. I don't think anyone's created this yet, but perhaps it has indeed already been done: when an area has more or less been cleared, its nest killed, etc., have a table of NPCs (both hostile and non-hostile) that would naturally be attracted to this newly-tamed area, based upon survival preferences (i.e., a lich lord may have been envying a crypt you've cleared for some time and has decided to make it his new home). It could become as complex as you'd have the budget to do: frontiersmen, dragon dens, infestations, relatively peaceful meadows with good game hunting, garrisons, evolving and living settlements, etc. Build the system that they aren't just random annoyances, but actual well-designed areas -with scripted and intelligent NPCs, merchants, quests, hideouts, monster pits…the works- that are appropriate to their environment. There could even be battles for said territory between rivaling factions. Perhaps a whole game system could be built around this, while keeping it an RPG and not a sim. It could keep the budget in line by not having to create these massive worlds; just have a world that is alive, adaptable, custom designed, and dynamic. The problem with even the biggest world is that once you've made it safe, it's as sterile as a hospital, even if you dump a few respawns into the mix.
That's just a little idea I've had for a while. I'm sure there are better ones: there is much room for improvement in this area!