Polymeric　prodrugs,　synthesized　by　conjugating　chemotherapeutic　agents　to　functional　polymers,　have　been　extensively　investigated　and　employed　for　safer　and　more　efficacious　cancer　therapy.　By　rational　design,　a　pH　and　reduction　dual-sensitive　dextran-di-drugs　conjugate　(oDex-g-Pt+DOX)　was　synthesized　by　the　covalent　conjugation　of　Pt　(IV)　prodrug　and　doxorubicin　(DOX)　to　an　oxidized　dextran　(oDex).　Pt　(IV)　prodrug　and　DOX　were　linked　by　the　versatile　efficient　esteri-fication　reactions　and　Schiff　base　reaction,　respectively.　oDex-g-Pt+DOX　could　self-assemble　into　nanoparticles　with　an　average　diameter　at　around　180　nm.　The　acidic　and　reductive　(GSH)　environment　induced　degradation　and　drug　release　behavior　of　the　resulting　nanoparticles　(oDex-g-Pt+DOX　NPs)　were　systematically　investigated　by　optical　experiment,　DLS　analysis,　TEM　measurement,　and　in　vitro　drugs　release　experiment.　Effective　cellular　uptake　of　the　oDex-g-Pt+DOX　NPs　was　identified　by　the　human　cervical　carcinoma　HeLa　cells　via　confocal　laser　scanning　microscopy.　Fur-thermore,　oDex-g-Pt+DOX　NPs　displayed　a　comparable　antiproliferative　activity　than　the　simple　combination　of　free　cisplatin　and　DOX　(Cis+DOX)　as　the　extension　of　time.　More　importantly,　oDex-g-Pt+DOX　NPs　exhibited　remarkable　reversal　ability　of　tumor　resistance　compared　to　the　cisplatin　in　cisplatin-resistant　lung　carcinoma　A549　cells.　Take　advantage　of　the　acidic　and　reductive　microenvironment　of　tumors,　this　smart　polymer-dual-drugs　conjugate　could　serve　as　a　promising　and　effective　nanomedicine　for　combination　chemotherapy.　©　2021　by　the　authors.　Licensee　MDPI,　Basel,　Switzerland.