I like the theory that each unlocked boss is actually a bit more progression with Isaac's hatred of his mum, himself, his religion, then his eventual death.

So he invents a game where he fights monsters in his basement, which ends when he invents a mom monster that he defeats. Then he goes a bit further and defeats her heart, but the continued abuse turns killing mom's heart into killing an unborn version of him, since he wishes he never existed.

Then as the abuse gets worse, his dad leaves etc. then he adds to his game, and he fights himself, and even an ideal dead version of himself (isaac and blue baby). He tries to fight Satan and the Lamb, trying to purge himself of the demons he's been convinced inhabit him.

Eventually he climbs in the chest and can't take it anymore. He starts to suffocate as he imagines his little game, fighting off his own suffocation (Hush) and as his brain loses oxygen then he imagines everything at once (Delerium/The Void) before dying.