I’d use her in none other than Nobilis. I see Madonna as an anchor for a Power of pop music, pop culture or other related fields. A plot for a game could revolve around her continual renaissances…is this something that the Power who has her anchored is doing? And what if this meddling conflicts with other anchors and Power’s plans for entertainment? How much is Madonna aware of the Nobilis world, anyhow?
A chameleon, ever-fascinating person that’s perfect as a “real-world” NPC to be dropped into the Nobilis realm. While, sure, the bit with doing famous people as anchors or Powers can be overdone, the GWB (from what I have read of it) does it anyway–Helen of Troy, Newton, and others.