Engineering a Second‐Order DNA Logic‐Gated Nanorobot to Sense and Release on Live Cell Membranes for Multiplexed Diagnosis and Synergistic Therapy

Tumor biomarker-based theranostics have achieved broad interest and success in recent years. However, single biomarker-based recognition can cause false-positive feedback, including the on-target off-tumor phenomenon, in the absence of tumor-specific antigen. Multibiomarker-based recognition molecules often elicit nonspecific and undesired internalization when they bind to "bystander" cells. We report a universal DNA tetrahedral scaffold (DTS) that anchors on the cell membrane to load multiple aptamers and therapeutics for precise and effective theranostics. This DNA logic-gated nanorobot (DLGN) not only facilitates precise discrimination among five cell lines, but also triggers synergistic killing of effector aptamer-tethered synergistic drugs (EASDs) to target cancer cells. Logic-gated recognition integrated into aptamer-functionalized molecular machines will prompt fast tumor profiling, in situ capture and isolation, and safe delivery of precise medicine.