Hepatocellular　carcinoma　(HCC)　is　one　of　the　most　common　and　deadliest　malignancy　cancers,　which　remains　a　major　global　health　problem.　At　present,　over　50%　of　patients　with　HCC　have　implemented　systemic　therapies,　such　as　interventional　therapy　or　local　chemotherapy　that　are　scarcely　effective　and　induce　serious　side　effects　to　the　remaining　normal　liver,　further　limiting　their　clinical　outcomes.　Herein,　a　tumor　microenvironment　triggered　cascade-activation　nanoplatform　(A-NPLap/TPZ)　is　prepared　based　on　beta-lapachone　(beta-Lap)　and　tirapazamine　(TPZ)　for　the　synergistic　therapy　of　HCC.　The　A-NPLap/TPZ　exerts　its　targeting　effect　by　binding　to　the　receptor　of　tumor　cells　with　an　external　aptamer.　In　the　tumor　microenvironment,　the　nanoplatform　can　realize　H2O2-triggered　disassembly　to　release　beta-Lap　and　TPZ.　The　released　beta-Lap　generates　ROS　to　induce　tumor　cell　apoptosis　under　the　catalysis　of　the　tumor　cell　over-expressed　NAD(P)H-quinone　oxidoreductase-1　(NQO1)　enzyme.　In　this　process,　oxygen　is　consumed　to　intensify　tumor　hypoxia,　and　eventually　cascade　activates　TPZ　to　exert　the　anti-tumor　effect.　The　studies　in　vitro　and　in　vivo　consistently　demonstrate　that　the　as-prepared　A-NPLap/TPZ　nanoplatform　possesses　an　excellent　synergistic　anti-tumor　effect.　This　design　of　nanoplatform　with　cascade　activation　effect　provides　a　promising　strategy　for　HCC　treatment.