Chiral Interaction Is a Decisive Factor To Replace d-DNA with l-DNA Aptamers.

Nucleic acid aptamers have been widely used in various fields such as biosensing, DNA chip, and medical diagnosis. However, the high susceptibility of nucleic acids to ubiquitous nucleases reduces the biostability of aptamers and limits their applications in biological contexts. Therefore, improving the biostability of aptamers becomes an urgent need. Herein, we present a simple strategy to resolve this problem by directly replacing the d-DNA-based aptamers with left-handed l-DNA. By testing several reported aptamers against respective targets, we found that our proposed strategy stood up well for nonchiral small molecule targets (e.g., Hemin and cationic porphyrin) and chiral targets whose interactions with aptamers are chirality-independent (e.g., ATP). We also found that the l-DNA aptamers were indeed endowed with greatly improved biostability due to the extraordinary resistance of l-DNA to nuclease digestion. With respect to other small-molecule targets whose interactions with aptamers are chirality-dependent (e.g., kanamycin) and biomacromolecules (e.g., tyrosine kinase-7), however, the proposed strategy was not entirely effective likely due to the participation of the DNA backbone chirality into the target recognition. In spite of this limitation, this strategy indeed paves an easy way to screen highly biostable aptamers important for the applications in many fields.