Advances in Therapeutic _L-Nucleosides and _L-Nucleic Acids with Unusual Handedness

Nucleic-acid-based small molecule and oligonucleotide therapies are attractive topics due to their potential for effective target of disease-related modules and specific control of disease gene expression. As the non-naturally occurring biomolecules, modified DNA/RNA nucleoside and oligonucleotide analogues composed of _L-(deoxy)riboses, have been designed and applied as innovative therapeutics with superior plasma stability, weakened cytotoxicity, and inexistent immunogenicity. Although all the chiral centers in the backbone are mirror converted from the natural _D-nucleic acids, _L-nucleic acids are equipped with the same nucleobases (A, G, C and U or T), which are critical to maintain the programmability and form adaptable tertiary structures for target binding. The types of _L-nucleic acid drugs are increasingly varied, from chemically modified nucleoside analogues that interact with pathogenic polymerases to nanoparticles containing hundreds of repeating _L-nucleotides that circulate durably in vivo. This article mainly reviews three different aspects of _L-nucleic acid therapies, including pharmacological _L-nucleosides, Spiegelmers as specific target-binding aptamers, and _L-nanostructures as effective drug-delivery devices.