Enhanced Sensitivity of Cell Identification in Complex Environments Using Chirally Inverted L‐DNA‐Based Logic Devices

Abstract Accurate identification and isolation of target cells are crucial for precision diagnosis and treatment. DNA aptamer‐based logic devices provide a distinct advantage in this context, as they can logically analyze multiple cell surface markers with high efficiency. However, the susceptibility of natural DNA (D‐DNA) to degradation can compromise the sensitivity and specificity of these devices, potentially leading to false‐positive and false‐negative results, particularly in complex biological environments. To address this issue, dual‐ and triple‐aptamer‐based cell‐surface logic devices are designed and developed using mirror‐image L‐DNA, a chiral molecule of D‐DNA with high biostability. These devices allow for simultaneous analysis of multiple cell surface proteins, achieving greater specificity in cell identification and isolation than D‐DNA‐based logic devices. The L‐DNA probes realized 98.7% and 70.5% sensitivities in FBS buffer with dual‐ and triple‐aptamer‐based logic devices for target cell identification, while D‐DNA probes only showed 27.9% and 0.1%. It is believed that the high stability of L‐DNA and the high efficiency of the devices for labeling cell subpopulations will have broad applications in the life sciences, biomedical engineering, and personalized medicine.