Precisely because it's well-worn territory, the low-hanging fruit has all been picked, and the art is in coming up with a punchline that feels new or original.
"The Mystery of the Yellow Room," published in 1908 and considered one of the best of its time, might seem downright formulaic more than a century later, because so many variations have been published since.
So the challenge for the writer of a locked-room mystery in the 21st century is to work within the boundaries of the premise but still make it feel, to the reader, that the climax is surprising or otherwise novel.