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

Abstract 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.