Membrane-anchored DNA nanodevice with allosteric aptamer arms enables parallel probing and on-site drug delivery
DNA-based molecular computation enables targeting of cells via multiple surface receptors. However, existing platforms are often limited to single-receptor detection per operation or rely on freely diffusing components, a common source of off-target interference. Here we show an intelligent DNA nanodevice (DND) that integrates multivalent recognition, logic‑gated computation, and spatially precise drug delivery in a single nanostructure. The DND comprises a doxorubicin-loaded tetrahedral DNA framework (tFNA@Dox) connected via three allosteric aptamer arms to a cholesterol-modified membrane anchor. Simultaneous binding of all three aptamers triggers an AND‑logic gate, releasing tFNA@Dox specifically at the target cell membrane. This localized sense‑and‑act mechanism maximizes therapeutic specificity and minimizes systemic exposure. In tumor-bearing mice, DND@Dox effectively accumulated in tumors, significantly inhibited tumor growth under local and systemic administration, and reduced systemic toxicity. This work establishes a versatile platform for logic‑controlled, multimarker‑guided cancer theranostics. DNA device-based targeting has huge potential but can be limited by single target recognition resulting in off target effects. Here, the authors develop a DNA nanodevice that anchors to cell membranes and releases chemotherapy only when three specific cancer markers are detected simultaneously.