Dynamic Modulation of Interactions Between Hydrophobic Tag‐Conjugated DNA Nanoprobes and Cell Membrane Facilitates ATP Imaging in the Tumor Microenvironment

Abstract Conjugating hydrophobic tags to oligonucleotides facilitates the swift and efficient creation of membrane‐anchored DNA nanoprobes. However, the membrane‐anchoring of these hydrophobic tag‐conjugated DNA nanoprobes (HT‐DNPs) lacks specificity among different cell types. To address this challenge, we herein report a conformational switching‐based strategy for selectively anchoring HT‐DNPs to target cells. In our design, HT‐DNPs with extended or compact conformations possess weak or strong interactions with cell membrane, respectively. Thus, interactions between HT‐DNPs and cell membrane can be dynamically controlled by altering the conformation of HT‐DNPs. Initially, the extended HT‐DNPs exhibit poor membrane‐anchoring ability that is impute to their weak hydrophobic interactions with cell membrane. However, in slightly acidic conditions, HT‐DNPs intercalated with DNA i‐motif‐forming sequences can fold into a compact conformation and exhibit strong hydrophobicity, thus achieving selective and efficient anchoring of HT‐DNPs to target cells in such environments. Utilizing this method, we constructed HT‐DNPs for imaging of ATP in the tumor microenvironment (TME). Our results indicate that these HT‐DNPs can effectively accumulate at tumor sites for specific ATP imaging following intravenous injection. This strategy paves new avenues for the selective and efficient functionalization of target cells with various membrane‐anchored DNA nanostructures, including DNA nanoprobes, DNA nanocircuits, and DNA nanomachines.