This would be an interesting hack:
Capture the data going between BN and your Nook and reverse engineer the Wireless Protocol that the Nook sends/receives in the store. Then you could create your own Web Server at home that would let you upload content you want on your Nook (ie. custom new feeds, customized newspaper sort of like Calibre does, send your EPUB books to your Nook, manage your Nook purchased book library w/o having to log into BN.com, etc).
Not sure how possible this would be, my guess is that there is some authentication/encryption involved (assuming BN did it right) so this sort of hack may not be trivial.
Anyone captured the data going in and out of the Nook yet?
Kovid, feel like taking on another additional feature for Calibre?