Endogenous dual miRNA-triggered dynamic assembly of DNA nanostructures for in-situ dual siRNA delivery

A theranostic strategy of multiple microRNA (miRNA)-triggered in-situ delivery of small interfering RNA (siRNA) can effectively improve the precise therapy of cancer cells. Benefiting from the advantages of programmability, specific molecular recognition, easy functionalization and marked biocompatibility of DNA nanostructures, we designed a three-dimensional (3D) DNA nano-therapeutic platform for dual miRNA-triggered in-situ delivery of siRNA. The 3D DNA nanostructure (TY1Y2) was constructed based on the self-assembly of a DNA tetrahedra scaffold, two sets of Y-shaped DNA (Y1 and Y2), and EpCAM-aptamer which functionalized as the ligand molecule for the recognition of specific cancer cells. After being specifically internalized into the targeted cancer cells, TY1Y2 was triggered by two endogenous miRNAs (miR-21 and miR-122), resulting in the generation of strong fluorescence resonance energy transfer fluorescent signal for dual miRNAs imaging. Meanwhile, the therapeutic siRNAs (siSurvivin and siBcl2) could also be in-situ generated and released from TY1Y2 through the strand-displacement reactions for the synergistic gene therapy of cancer cells. This 3D DNA nanostructure integrated the specific imaging of endogenous biomarkers and the in-situ delivery of therapeutic genes into the multifunctional nanoplatform, revealing the promising applications for the diagnosis and treatment of cancer. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at 10.1007/s40843-022-2420-y.