I'm possibly going to be called out with this (With several links to past games that I don't know about), but what about an RPG in Purgatory? I'm not thinking Silent Hill, but something completely devoid of human influence and inhabited by Jinn/Spirits/Walt Disney. Laws of physics would count for nothing, and progressing further into the Nether could leave your character slowly losing his/her/its strength as it distances itself from their entrance, allowing corruption to set in slowly. Over the course of the campaign you would (in true RPG fashion) find & recruit a number of individuals who exist within this plane.
Please note I've thought of this on the spot, meaning I don't know why the main character even ventures here or whether I'd send another character with them. They could be here for; exploration purposes (Scientific breakthrough allowing for travel to purgatory/another plane?), war against a hostile force (Although I think war has been over done countless times, and YOU are the one trespassing in someone else's home, so you could be interpreted as the aggressor), or entrance is found by pure chance/through some anomaly in nature... though that doesn't really work with the idea entirely.
The gradual corruption culminates in the main character losing their mind as the corruption physically manifests itself in your body, distorting it and altering your attacks, personality and power overall. You turn on whatever comrades you have recruited up to this point, killing one (or more) of them when you discover that your only entry point back home has been severed when those on the other end discover what has happened to you, and abandon you as a final method of quarantine. The main character loses all hope: condemned from his own home, terrified at what they are becoming with their final hope fleeing for their own sakes, away from this demonic thing.
Those you have recruited along the journey now side against you, angered or distraught at the death of one of their own at their friends (Your) hands. They now promise to alleviate your pain by putting you down and side against you. This is important now as you, the player, are given the choice of playing as either the former main character, who is now isolated from all other interaction but continues to grow in power, seeking to destroy anything he comes across and hunting down the former team, OR play as the now beleaguered characters you recruited, who grow in power and gain abilities as normal, but now have to face a foe who's power is increasing at a freakish rate, meaning you have to gather more forces to face him/her/it eventually (The forces you gather could be former antagonists, who's existence and homes are under threat from the former main character, and are now seen as protagonists).
Any constructive critisism is very much appreciated... though it'll serve no purpose. Please know that I've only thought this up whilst being sat in this thread and brainstorming it, so kindly keep your "OMG THTS SHIT" comments to yourself, thanks =D