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.[Figure　not　available:　see　fulltext.]　©　2023,　Science　China　Press.