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.　©　2022　The　Royal　Society　of　Chemistry