Multiple　drug-resistance　mechanisms　originate　from　defensive　pathways　in　cancer　and　are　associated　with　the　unsatisfied　efficacy　of　chemotherapy.　The　combination　of　small　interfering　RNA　(siRNA)　and　chemotherapeutics　provides　a　strategy　for　reducing　drug　efflux　but　requires　more　delivery　options　for　clinical　translation.　Herein,　multidrug　resistance　protein　1　(MDR1)　siRNA　is　used　as　the　skeleton　to　assemble　chemotherapeutic　cisplatin　(CDDP)　and　divalent　copper　ion　(Cu2+)　for　constructing　a　carrier-free　Cu-siMDR-CDDP　system.　Cu-siMDR-CDDP　specifically　responds　and　disassembles　in　the　acidic　tumor　microenvironment　(TME).　The　released　CDDP　activates　cascade　bioreactions　of　NADPH　oxidases　and　superoxide　dismutase　to　generate　hydrogen　peroxide　(H2O2).　Then　a　Cu-2(+)-catalyzed　Fenton-like　reaction　transforms　H2O2　to　hydroxyl　radicals　(HO　center　dot)　and　causes　glutathione　(GSH)　depletion　to　disrupt　the　redox　adaptation　mechanism　of　drug-resistant　cancer　cells.　Besides,　delivery　of　MDR1　siRNA　is　facilitated　by　HO　center　dot-triggered　lysosome　destruction,　thus　inhibiting　P-glycoprotein　(P-gp)　expression　and　CDDP　efflux.　The　unique　design　of　Cu-siMDR-CDDP　is　to　exploit　siRNA　as　building　blocks　in　regulating　the　self-assembly　behavior,　and　integration　of　functional　units　simultaneously　alleviates　limitations　caused　by　drug-resistance　mechanisms.　Such　a　carrier-free　system　shows　synergistic　chemo/chemodynamic　RNA　interference　therapy　in　suppressing　tumor　growth　in　vivo　and　has　the　reference　value　for　overcoming　drug　resistance.