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Recent progresses in organic chemistry and molecular biology have allowed the emergence of numerous new applications of nucleic acids that markedly deviate from their natural functions. Particularly, DNA and RNA molecules—coined aptamers—can be brought to bind to specific targets with high affinity and selectivity. While aptamers are mainly applied as biosensors, diagnostic agents, tools in proteomics and biotechnology, and as targeted therapeutics, these chemical antibodies slowly begin to be used in other fields. Herein, we review recent progress on the use of aptamers in the construction of smart DNA origami objects and MRI and PET imaging agents. We also describe advances in the use of aptamers in the field of neurosciences (with a particular emphasis on the treatment of neurodegenerative diseases) and as drug delivery systems. Lastly, the use of chemical modifications, modified nucleoside triphosphate particularly, to enhance the binding and stability of aptamers is highlighted.

Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker Plasmodium vivax lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of P. vivax over Plasmodium falciparum lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.

Rolling circle amplification (RCA) is a robust way to generate DNA constructs, which are promising materials for biomedical applications including drug delivery because of their high biocompatibility. To be employed as a drug delivery platform, however, the DNA materials produced by RCA need to be shaped into nanoparticles that display both high cellular uptake efficiency and nuclease resistance. Here, we showed that the DNA nanoparticles (DNPs) can be prepared with RCA and modified nucleotides that have side-chains appended on the nucleobase are capable of interacting with the DNA strands of the resulting RCA products. The incorporation of the modified nucleotides improved cellular uptake efficiency and nuclease resistance of the DNPs. We also demonstrated that these DNPs could be employed as carriers for the delivery of a photosensitizer into cancer cells to achieve photodynamic therapy upon irradiation at both the in vitro and in vivo levels.

Aromatic \\(\\)-stacking interactions play an important role in both natural and artificial systems, influencing processes such as charge separation in photosynthesis and charge transport in organic semiconductors. Controlling the geometry and distance between aromatic units is therefore crucial for tuning intermolecular interactions and charge-transfer efficiency. Due to their well-defined stacking geometry, paracyclophanes (PCPs) composed of two or more aromatic units connected by rigid linkers, provide an ideal platform for a systematic study of such effects. Despite extensive experimental studies of PCPs, a comprehensive and quantitatively validated theoretical description linking the structure with the electronic and optical properties is still missing. Here, we present an extensive computational and experimental investigation of the electronic and optical properties of homo-PCPs containing naphthalene diimide (NDI) or pyrene chromophores linked by bridges of varying length and rigidity. We introduce a robust methodology for an accurate simulation of the absorption and fluorescence spectra of PCPs based on a combined TD-DFT and CC2 approach, achieving excellent quantitative agreement with experiment. We also present and validate a fragment-based description of PCPs using the Frenkel exciton model. Such approach is valuable not only for interpretation of the electronic and optical properties of PCPs, but it can also significantly reduce the cost of the calculation while maintaining the accuracy of the supermolecular approach. This work establishes a quantitatively reliable framework linking structure, excitonic coupling, and charge-transfer interactions in PCPs with optical properties, providing design principles for next-generation optoelectronic materials.