Abstract The modulation of intracellular reactive oxygen species (ROS) levels is crucial for cellular homeostasis and determination of cellular fate. A sublethal level of ROS sustains cell proliferation, differentiation and promotes tumor metastasis, while a drastic ROS burst directly induces apoptosis. Herein, surface-oxidized arsenene nanosheets (As/As x O y NSs) with type II heterojunction are fabricated with efficient ·O 2 − and 1 O 2 production and glutathione consumption through prolonging the lifetime of photo-excited electron-hole pairs. Moreover, the portion of As x O y with oxygen vacancies not only catalyzes a Fenton-like reaction, generating ·OH and O 2 from H 2 O 2 , but also inactivates main anti-oxidants to cut off the “retreat routes” of ROS. After polydopamine (PDA) and cancer cell membrane (M) coating, the engineered As/As x O y @PDA@M NSs serve as an intelligent theranostic platform with active tumor targeting and long-term blood circulation. Given its narrow-band-gap-enabled in vivo fluorescence imaging properties, As/As x O y @PDA@M NSs could be applied as an imaging-guided non-invasive and real-time nanomedicine for cancer therapy.