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bioRxiv · 10.64898/2026.05.20.726533

Mirror-Image L-DNA Nanocubes for Stable and Targeted Multimodal Drug Delivery

Farkaly, T.·Wu, S.·Dantsu, Y.·Tapash, A.·Zhang, W.
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Abstract

Nucleic acid nanostructures provide programmable architectures for molecular delivery but remain limited by rapid nuclease degradation, poor in vivo persistence and inefficient intracellular cargo release. Here we report a mirror-image L-DNA nanocube as a biologically persistent and modular therapeutic delivery platform. The nanocube self-assembles from synthetic L-DNA oligonucleotides into a structurally defined architecture that exhibits substantially enhanced resistance to enzymatic degradation and prolonged stability under physiological conditions compared with the corresponding D-DNA nanostructure. Surface functionalization with folic acid enables selective tumour targeting in vitro and in vivo. The L-DNA nanocube supports the delivery of chemically distinct therapeutic cargos, including doxorubicin, a bortezomib prodrug and MCL1-targeting small interfering RNA (siRNA). In tumour-bearing mice, L-DNA nanocube-mediated delivery improves therapeutic efficacy while reducing systemic toxicity relative to free drug and D-DNA nanocube controls. For siRNA delivery, we engineer a pH-responsive release mechanism that promotes endosomal escape and cytosolic cargo localization, as visualized by cryo-electron tomography, resulting in efficient gene silencing. Together, these results establish mirror-image nucleic acid nanostructures as a class of biologically functional nanomaterials for programmable intracellular therapeutic delivery.

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Farkaly, T., Wu, S., Dantsu, Y., Tapash, A., Zhang, W.. 2026-05-22. Mirror-Image L-DNA Nanocubes for Stable and Targeted Multimodal Drug Delivery. https://doi.org/10.64898/2026.05.20.726533

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