Leveraging Aptamer-Based DNA Nanotechnology for Bioanalysis and Cancer Therapeutics

ConspectusAptamers are single-stranded DNA or RNA molecules composed of 15–80 nucleotides, obtained from a random oligonucleotide library via the systematic evolution of ligands by exponential enrichment (SELEX) technology. They can bind to a wide range of targets with high binding affinity and high specificity including metal ions, small molecules, proteins, cells, and even tissues. When compared to the commonly used antibodies, aptamers show better thermal stability, a smaller molecular weight, easier modification, and little batch-to-batch variation by chemical synthesis. These unique merits position aptamers as promising molecular tools in biomedical applications, spanning biosensing, bioimaging, disease diagnosis, targeted chemotherapy, and cancer immunotherapy. However, as chemically synthesized oligonucleotides, aptamers would be degraded by nucleic acid degrading enzymes (e.g., endonucleases or exonucleases) presented in the blood circulation, thereby reducing the stability and activity. Another limitation is the rapid clearance by the liver and kidneys, reducing their circulation life and bioavailability. Recent progress in DNA nanotechnology has garnered global interest, with emerging interdisciplinary applications across chemistry, materials, biology, and medicine. The fundamental of DNA self-assemblies and DNA dynamic operation is Watson–Crick base pairing assisted by in silico programmable design. As functional building blocks, aptamers can inherently enable great potential with DNA nanotechnology including bioanalysis, targeted drug delivery, and cancer immunotherapy. Therefore, aptamer-based DNA nanotechnology would arouse important interests in future research.As molecular medicine offered personalized and precise diagnostic and therapeutic solutions, in this Account, we focus on the research advancements of leveraging DNA aptamer with DNA nanotechnology for molecular medicine, particularly our recent research progress. Often referred to as chemical antibodies, aptamers enable DNA nanotechnology for bioanalysis and cancer therapeutics. Thus, two parts are discussed in this Account: initially, we discuss the molecular modifications of aptamers by cyclization and nucleotide backbone engineering. The aptamer-tethered DNA nanostructures then were constructed for cell identification and bioanalysis. To perform intelligent cancer diagnosis, we detailed three formulations of aptamer-involved molecular computation. In the last part, we focus on aptamer-based targeted chemotherapy and immunotherapy. Based on the covalent coupling strategy, we report a series of aptamer drug conjugates. Similarly, by employing cyclization strategy, the circular bivalent aptamer drug conjugates are discussed. Next, as small molecule drug delivery systems encounter challenges related to insufficient biological stability, particularly in terms of vulnerability to enzyme cleavage and short circulation time in vivo, aptamer-tethered nanomedicines are introduced for targeted chemotherapy. The immunotherapy section includes tumor vaccines, adoptive cell immunotherapy, and immune checkpoint blockade. Finally, we propose the challenges and opportunities in bioapplications of aptamer-based DNA nanotechnology.