Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions. Herein, we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop. The di-selenide-bridged prod-rug synthesized from vitamin E succinate and methotrexate (MTX) self-assembles into nanoparticles (VSeM); decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time. Upon reaching tumor sites, acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake. Afterward, the VSeM could be dissoci-ated in response to intracellular ROS to trigger VES/MTX release; then the released VES could produce extra ROS to accelerate the collapse of VSeM. Finally, the excessive ROSproduced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy. Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.