Zhang, W.; Zhang, Y.; Dantsu, Y.

The development of stable and efficient drug delivery systems is crucial for advancing therapeutic applications. Here, we present a novel approach involving the construction of a mirror-image RNA (L-RNA) nanostructure to enhance biostability and drug delivery efficiency. Specifically, we utilized L-RNA to create a three-way junction structure, which was then conjugated with small interfering RNA (siRNA) and chemotherapy agents for targeted drug delivery. Our findings demonstrate that this L-RNA nanostructure significantly improves therapeutic efficiency due to its enhanced stability compared to natural D-RNA. In additionally, the conjugated folic acid (FA) group dramatically enhance the specificity and endosomal escape efficiency of the nanoparticles, which benefit the combinatorial drug delivery. This work highlights the potential of mirror-image RNA nanostructures as robust platforms for drug delivery applications.