The low selectivity of currently available photosensitizers, which causes the treatment-related toxicity and side effects on adjacent normal tissues, is a major limitation for clinical photodynamic therapy (PDT) against cancer. Moreover, since PDT process is strongly oxygen dependent, its therapeutic effect is seriously hindered in hypoxic tumor cells. To overcome these problems, a cell-specific, H2O2-activatable, and O-2-evolving PDT nanoparticle (HAOP NP) is developed for highly selective and efficient cancer treatment. The nanoparticle is composed of photosensitizer and catalase in the aqueous core, black hole quencher in the polymeric shell, and functionalized with a tumor targeting ligand c(RGDfK). Once HAOP NP is selectively taken up by alpha v beta 3 integrin-rich tumor cells, the intracellular H2O2 penetrates the shell into the core and is catalyzed by catalase to generate O-2, leading to the shell rupture and release of photosensitizer. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen (O-1(2)) in the presence of O-2 to kill cancer cells. The cell-specific and H2O2-activatable generation of O-1(2) selectively destroys cancer cells and prevents the damage to normal cells. More significantly, HAOP NP continuously generates O-2 in PDT process, which greatly improves the PDT efficacy in hypoxic tumor. Therefore, this work presents a new paradigm for H2O2-triggered PDT against cancer cells and provides a new avenue for overcoming hypoxia to achieve effective treatment of solid tumors.