Probably Isabelle and Tom Nook. I always thought it was weird that these characters who were essentially the face of the marketing for the games were always the ones that you couldn't actually interact with in any meaningful ways.
That being said, I've thought before about how NPC's could be improved if they had more traits of regular villagers. For example, if they had a house that they went home to every night when they closed up shop, or if their house is part of their shop, there would be living quarters you could visit at certain times. Also, let the NPC's have personalities, emotions, and motivations that can both benefit and hurt the player. On some days, shopping may be more difficult because Tom Nook is in a bad mood. In other days, Isabelle might be feeling down and have a hard time fulfilling her duties as mayor's assistant or whatever. Other days she might be extra productive because she had a pleasant night out the previous day. (EDIT- Something I just thought of: Since she is a bit of a workaholic, have her moods shift based on how much workload you actually put on her, and force the players to balance between not overloading her while also keeping her occupied with something.) Or, remember in the GameCube game where if you accidentally press cancel when you were handing over an item to a villager, they would get mad? While I'm glad that they no longer IMMEDIATELY get mad at you in subsequent games, I always thought that would have worked really well for NPC's like the little girl that you can sell items to on the island in New Leaf.
These changes might be polarizing to some players, because they make the game more complex, but I generally feel like they would benefit the series because... well, it makes the games more complex. As much as I love New Leaf, I feel like coming from the GameCube games, the villagers and NPC's alike feel considerably more neutered by comparison, and I'd love for the series to refine and expand upon interactive elements as opposed to chopping them like in more recent games.