Small　interfering　RNA　(siRNA)　is　an　effective　therapeutic　to　regulate　the　expression　of　target　genes　in　vitro　and　in　vivo.　Constructing　a　siRNA　delivery　system　with　high　serum　stability,　especially　responsive　to　endogenous　stimuli,　remains　technically　challenging.　Herein　we　develop　anti-degradation　Y-shaped　backbone-rigidified　triangular　DNA　bricks　with　sticky　ends　(sticky-YTDBs)　and　tile　them　onto　a　siRNA-packaged　gold　nanoparticle　in　a　programmed　fashion,　forming　a　multi-functional　three-dimensional　(3D)　DNA　shell.　After　aptamers　are　arranged　on　the　exterior　surface,　a　biocompatible　siRNA-encapsulated　core/shell　nanoparticle,　siRNA/Ap-CS,　is　achieved.　SiRNAs　are　internally　encapsulated　in　a　3D　DNA　shell　and　are　thus　protected　from　enzymatic　degradation　by　the　outermost　layer　of　YTDB.　The　siRNAs　can　be　released　by　endogenous　miRNA　and　execute　gene　silencing　within　tumor　cells,　causing　cell　apoptosis　higher　than　Lipo3000/siRNA　formulation.　In　vivo　treatment　shows　that　tumor　growth　is　completely　(100%)　inhibited,　demonstrating　unique　opportunities　for　next-generation　anticancer-drug　carriers　for　targeted　cancer　therapies.　Small　interfering　RNA　(siRNA)　is　used　to　regulate　gene　expression　for　therapeutic　purposes,　but　the　design　of　stable　and　efficient　siRNA　delivery　systems　is　challenging.　Here,　the　authors　develop　a　siRNA-encapsulated　and　aptamer-incorporated　core/shell　nanoparticle　for　controlled　siRNA　delivery,　with　high　stability,　tumor-specific　targeting　and　long　circulation　time.