The most difficult thing will be crossing bridges. Are you able to walk any? Even if you are able to walk/cross one bridge, that will be some help. We stayed at the Europa & Regina. Loved the location. There are restaurants, plenty of shops withouts crossing any bridges. If you cross one bridge, you can get to St. Marks Square and the Opera House area where more restaurants are located. We ate at Vino Vino for dinner, and it was delicious. I like the idea of taking the Vapretto to St. Marks Square. You can ask your Hotel to arrange a porter to help with the luggage from there. Europa and Regina was wonderful in helping us arrange things. Venice is not very handicapped accessible, and it's a shame, because they could make it more. But you can still have a great time here, and it is definitely doable as long as your expectations are realistic and don't expect to travel everywhere by wheelchair. We were worried about the stone streets, but they have been walked so much over hundreds of years, they are smooth, for the most part (at least the parts around where we stayed).