Proteolysis-targeting　chimeras　(PROTACs)　are　dual-functional　molecules　composed　of　a　protein　of　interest　(POI)　ligand　and　an　E3　ligase　ligand　connected　by　a　linker,　which　can　recruit　POI　and　E3　ligases　simultaneously,　thereby　inducing　the　degradation　of　POI　and　showing　great　potential　in　disease　treatment.　A　challenge　in　developing　PROTACs　is　the　design　of　linkers　and　the　modification　of　ligands　to　establish　a　multifunctional　platform　that　enhances　degradation　efficiency　and　antitumor　activity.　As　a　programmable　and　modifiable　nanomaterial,　DNA　tetrahedron　can　precisely　assemble　and　selectively　recognize　molecules　and　flexibly　adjust　the　distance　between　molecules,　making　them　ideal　linkers.　Herein,　we　developed　a　multivalent　PROTAC　based　on　a　DNA　tetrahedron,　named　AS-TD2-PRO.　Using　DNA　tetrahedron　as　a　linker,　we　combined　modules　targeting　tumor　cells,　recognizing　E3　ligases,　and　multiple　POI　together.　We　took　the　undruggable　target　protein　signal　transducer　and　activator　of　transcription　3　(STAT3),　associated　with　the　etiology　and　progression　in　a　variety　of　malignant　tumors,　as　an　example　in　this　study.　AS-TD2-PRO　with　two　STAT3　recognition　modules　demonstrated　good　potential　in　enhancing　tumor-specific　targeting　and　degradation　efficiency　compared　to　traditional　bivalent　PROTACs.　Furthermore,　in　a　mouse　tumor　model,　the　superior　therapeutic　activity　of　AS-TD2-PRO　was　observed.　Overall,　DNA　tetrahedron-driven　multivalent　PROTACs　both　serve　as　a　proof　of　principle　for　multifunctional　PROTAC　design　and　introduce　a　promising　avenue　for　cancer　treatment　strategies.　©　2025　American　Chemical　Society.