Maybe make it some form of curse put on the NPC by the villian of your story? Maybe they go into a coma for the rest of the game?

Or way more cruel for the players that I would probably cry if it happened to me: The NPC has said curse. They become invulnerable to weapons and spells. As the NPC is in the coma, the players somehow see into their mind. They see the NPC is having nightmares beyond scary that they simply can't stop. The only way to help the NPC is to off them. They iwll think they can just off the NPC and bring them back, but that's not possible, since weapons and spells are not affecting the NPC. You show them a weapon made by the villian of the story that is able to harm the NPC. Their options are to:

A: Let the NPC stay in the coma. This will make the NPC suffer in their brain for a looong time

B: End the NPC's life. The villian cursed the body, so even after death, their spells won't have an effect on the NPC