Traditional　hepatocellular　carcinoma-chip　models　lack　the　cell　structure　and　microenvironments　necessary　for　high　pathophysiological　correlation,　leading　to　low　accuracy　in　predicting　drug　efficacy　and　high　production　costs.　This　study　proposed　a　decellularized　hepatocellular　carcinoma-on-a-chip　model　to　screen　anti-tumor　nanomedicine.　In　this　model,　human　hepatocellular　carcinoma　(HepG2)　and　human　normal　liver　cells　(L02)　were　co-cultured　on　a　three-dimensional　(3D)　decellularized　extracellular　matrix　(dECM)　in　vitro　to　mimic　the　tumor　microenvironments　of　human　hepatocellular　carcinoma　in　vivo.　Additionally,　a　smart　nanomedicine　was　developed　by　encapsulating　doxorubicin　(DOX)　into　the　ferric　oxide　(Fe3O4)-incorporated　liposome　nanovesicle　(NLV/Fe+DOX).　NLV/Fe+DOX　selectively　killed　78.59%　±　6.78%　of　HepG2　cells　through　targeted　delivery　and　synergistic　chemo-chemodynamic-photothermal　therapies,　while　the　viability　of　surrounding　L02　cells　on　the　chip　model　retained　high,　at　over　90.0%.　The　drug　efficacy　tested　using　this　unique　chip　model　correlated　well　with　the　results　of　cellular　and　animal　experiments.　In　summary,　our　proposed　hepatocellular　carcinoma-chip　model　is　a　low-cost　yet　accurate　drug-testing　platform　with　significant　potential　for　drug　screening.　©　2024　Elsevier　B.V.