Programmable DNA aptamer logic gates: from structural design to integrated systems for intelligent nanoscale biosensors.

DNA aptamer-based logic gates represent significant advances in molecular computing, enabling complex biological computations at the nanoscale. These systems leverage the unique programmable properties of DNA aptamers-short, single-stranded oligonucleotides with high specificity and binding affinity for diverse applications across fields such as clinical diagnostics, food/environmental monitoring, and targeted therapeutic delivery, garnering significant research interest in the past few decades. In this review, we first expand on the fundamentals of aptamers, including its SELEX process and post-SELEX modifications. We systematically examine the design principles and operation mechanisms of DNA aptamer-based logic gates, mainly AND, OR, INHIBIT and NOT as reported by researchers. Then, we highlight various logic gates based on different oligonucleotides spanning from intact and split aptamers to DNA origami architectures, DNA nanorobots, and G-quadruplex structural switches, bringing to light their applications across various fields. Recent innovations in multi-input/output gate cascades, CRISPR-Cas-integrated systems and signal amplification approaches are highlighted as key developments in DNA aptamer-based logic gates. Finally, we elucidate challenges relating to DNA aptamer-based systems such as aptamer performance, cross-reactivity in complex multi-input systems and the complexities of merging other systems to amplify output readability, among others, to the end that in addressing these challenges, we will be able to unlock the full potential of this system.