If they find DNA, experts can compare it to living relations to make sure it actually belongs to Leonardo, before testing samples from the grave in a similar way to how Richard III was identified after his body was found under a Leicester car park.
They are also hunting for the grave of his father in Florence, and mother in Milan, as another way of verifying the match. Once granted permission to exhume the remains, the team hope to reconstruct the face of Leonardo - if it is in fact him - from his skull to see how it compares with self-portraits, as well as studying his bones to learn more about diet and what caused his death, which has never been recorded.
Jesse Ausubel, vice-chairman of the Richard Lounsbery Foundation, which is funding the project, said: "It is well known that Leonardo used his fingers along with his brushes while painting, some prints of which have remained, and so it could be possible to find cells of his epidermis mixed with the colours.
"We stand to gain not only greater historical knowledge of Leonardo but possibly a reconstruction of his genetic profile, which could provide insights into other individuals with remarkable qualities."
Born in Vinci, Italy, in 1452, Leonardo foresaw and described innovations hundreds of years before their time, such as the helicopter and armoured tank. His artistic legacy includes the Mona Lisa and The Last Supper. Near the end of his life, Leonardo accepted an invitation from the French King, Francis I, to leave Italy and move to the Chateau du Clos Luc near Amboise, with some of his students, where he held the position of "first painter, engineer, and architect of the king". He died in Cloux on May 5, 1519, aged 67.