Cancer　stem　cells　(CSCs)　have　the　ability　to　transform　into　bulk　cancer　cells,　to　promote　tumor　growth　and　establish　tumor　metastasis.　To　effectively　inhibit　tumor　growth　and　prevent　metastasis,　treatments　with　conventional　chemotherapy　drugs　should　be　combined　with　CSC　targeted　drugs.　In　this　study,　we　describe　the　synthesis　and　characterization　of　a　new　amphiphilic　polymer,　hyaluronic　acid-cystamine-polylactic-co-glycolic　acid　(HA-SS-PLGA),　composed　of　a　hydrophobic　PLGA　head　and　a　hydrophilic　HA　segment　linked　by　a　bioreducible　disulfide　bond.　With　a　double　emulsion　method,　a　nano　delivery　system　was　constructed　to　deliver　doxorubicin　(DOX)　and　cyclopamine　(CYC,　a　primary　inhibitor　of　the　hedgehog　signaling　pathway　of　CSCs)　to　both　a　CD44-overexpressing　breast　CSC　subpopulation　and　bulk　breast　cancer　cells　and　allow　an　on-demand　release.　The　resulting　drug-loaded　NPs　exhibited　a　redox-responsive　drug　release　profile.　Dual　drug-loaded　particles　potently　diminished　the　number　and　size　of　tumor-spheres　and　HA　showed　a　targeting　effect　towards　breast　CSCs.　In　vivo　combination　therapy　further　demonstrated　a　remarkable　synergistic　anti-tumor　effect　and　prolonged　survival　compared　to　monotherapy　using　the　orthotopic　mammary　fat　pad　tumor　growth　model.　The　co-delivery　of　drug　and　the　CSC　specific　inhibitor　towards　targeted　cancer　chemotherapeutics　provides　an　insight　into　anticancer　strategy　with　facile　control　and　high　efficacy.