Nucleic acid molecules can fold into versatile three-dimensional geometries to target physiological molecules. The development of various advanced biotechnologies has enabled this rapid emerging field for disease treatment, especially after the unprecedented pandemic and prompt development of mRNA vaccines. However, some intractable challenges are still limiting nucleic acids’ clinical applications, including the quick degradation in vivo by the ubiquitous nucleases, and some nonspecific toxicity from the unintended RNA-protein interactions. To address these challenges, we propose to synthesize an innovative chemically modified mirror-image RNA molecule. This artificial RNA can be used to select advanced mirror-image aptamers to target disease ligands, as well as to construct stable nanodevices to effectively deliver therapy for cancer treatment. Its radically different chirality from native RNA makes it unrecognizable by any nucleases in plasma, leading to the greatly extended half-life in vivo. We introduce more chemical moieties into the mirror-image RNA backbone, and observe the thermal and structural stability enhancement by the rigidified L-ribose. Plus, the 2'-modificatins further expand the L-RNA’s physicochemical diversity as drugs, and this chemically modified mirror-image RNA has been applied to isolate advanced aptamers to target the critical RNA element of viral genome. Moreover, we have built up a novel L-RNA nanoparticle, which can carry multiple chemo- and gene therapies for specific drug delivery into human triple negative cancer (TNBC) cells. This mirror-image RNA-based nanoparticle demonstrates enhanced bioavailability, specificity and stability, which can provide a promising approach in TNBC clinical treatment. Our results demonstrate great potential in the application of this synthetic biological molecules, from the bench of basic science to the bedside of clinical disease treatment.

Mirror-image nucleic acids as next-generation therapeutics

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.