DNA Nanolock-Based Logic Gate-Directed Reciprocal Feedback for Stepwise Cell Typing and Combination Treatment

To achieve accurate molecular diagnosis and early-stage intervention of disease on demand, there is an urgent need for the monitoring of multiple biomarkers and multipath information acquisition in living cells. The DNA combinatorial logic gate is an appropriate strategy for providing a systematic proof of concept with comprehensive information and function. Herein, a modular DNA logic gate nanomachine is designed for sufficient multistep reciprocal cell identification and therapy via the iteration of simple logic operations. In this logic gate system, this main module is constructed by G-quadruplex-locked gold nanocages (AuNCs), serving dual functions of drug encapsulation and cell recognition. The logic system is composed of OR, XNOR, AND, and NOR gates employing two intracellular disease biomarkers (microRNA 21 and microRNA 155) as inputs and the fluorescence signal of doxorubicin (Dox) as an output. The output signals of the four logic gates are iterated to process the imaging analysis data from the complex matrix in the living cell. Via positive and negative reciprocal feedback, the series circuit of different gates enables different functions, including the preliminary screening and the distinction of the cell type. Through the mutual preliminary screening and further proof, this logic system achieves accurate identification of cells, controlled drug release, and photothermal treatment using the AuNC as a photothermal transducer. This DNA logic system broadens the applications of the biocomputing system in disease screening and logic-controlled treatment fields.