Membrane-Anchored pH-Responsive DNA Nanodevice Enhances Natural-Killer-Cell Interaction Specificity toward Tumor Cells

Cellular interactions mediated by membrane-associated proteins are crucial for cell-based therapies, yet achieving high specificity remains a significant challenge. In this work, we developed a nongenetic, tumor microenvironment (TME)-responsive DNA nanodevice to enhance the targeting precision of natural killer (NK) cells against tumor cells. This nanodevice comprises an amphiphilic DNA tetrahedral scaffold for NK-cell membrane anchoring and a CD71-specific aptamer incorporating a pH-sensitive DNA triplex for tumor targeting. Under normal physiological pH, the nanodevice maintains an inactive state, preventing off-target binding. Upon exposure to the acidic TME, the triplex structure stabilizes, enabling the aptamer to adopt a functional conformation for specific CD71 recognition. This TME-responsive tumor-associated antigen targeting strategy significantly enhances the specificity of NK cells in recognizing and lysing tumor cells.