Due to its tumor-specificity and limited side effects, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown great potential in cancer treatments. However, the short half-life of TRAIL protein and the poor death receptor (DR) expression of cancer cells severely compromise the therapeutic outcomes of TRAIL in clinical studies. Herein, a novel ROS-dependent TRAIL-sensitizing nanoplatform, CPT MV, with a Ce6-PLGA core and a TRAIL-modified cell membrane shell was explored to improve the in vivo circulation stability of TRAIL and to amplify TRAIL-induced apoptosis. CPT MV could produce ROS in the targeted cells upon laser irradiation to improve death receptor (DR)-5 expression and trigger Cyt c release from mitochondria. When engaged with TRAIL, the up-regulated DR5 could recruit more Fas-associated death domain (FADD) to transport the extrinsic apoptotic signal to the initiator caspase (caspase 8) and then the executioner caspase (caspase 3), while leaked Cyt c could trigger the intrinsic apoptotic pathway to further strengthen TRAIL-induced apoptosis. Therefore, the designed CPT MV could enhance TRAIL-mediated apoptosis driven by photo-triggered oxidative stress, which provides a very promising approach to clinically overcome tumor resistance to TRAIL therapy.