<span class="paragraphSection"><div class="boxTitle">Abstract</div>The expanded backbone chemistries of xeno-nucleic acids (XNAs) hold significant promise for emerging areas of synthetic biology and nanomaterials, but metal-mediated XNA interactions remain largely unexplored. Here, we use a combination of circular dichroism spectroscopy and mass spectrometry to show that XNAs can form Ag⁺-mediated duplex structures resembling their DNA counterparts. XNAs with a range of different backbone compositions are found to stabilize photoluminescent silver nanoclusters with spectral properties that can be tuned based on their respective backbone chemistry. The resistance of silver nanoclusters to nuclease digestion is also compared for DNA and XNAs. These results show that XNA backbone chemistry provides a new tool beyond nucleobase sequence for controlling and expanding the properties of nucleic acid-stabilized silver nanoclusters and metal-mediated DNA duplexes.</span>