The MacGuffin (heretofore known as MG) is shielded from being found, but the shielding isn't enough and if the MG remains in the same general vicinity long enough, its essence will become detectable. It also can't be destroyed. So those who would see it kept out of the wrong peoples hands have to keep the MG constantly on the move, forever. Of course, if it's ever used, or the shielding ever removed, it becomes locatable as well... (Using this in an upcoming campaign)
Similar to the above, the MG is always readily detectable and anyone who wants to can easily find it. As a result, it must be heavily guarded.
The MG is cursed. The only way to get rid of it is to get someone else to willingly take it. If destroyed, the bearer is killed and his/her soul erased. For extra difficulty, when giving it away the recipient must be aware of the nature of the MG.