A unique photosensitizer (PS), (PS)-P-ER, with intrinsic endoplasmic reticulum (ER)-targeting ability and low oxygen-depletion type-I photosensitivity, is developed and used as a scaffold to construct an activatable theranostic agent for precise photodynamic therapy (PDT). The ER-targeted feature coupled with type-I photosensitivity endows (PS)-P-ER with high phototoxicity toward tumor cells under both normoxic and hypoxic conditions. In addition, caging the phenol group of (PS)-P-ER with a nitroreductase-sensitive triggering group provided a hypoxia-activatable PS ((ER)PSIm) that is encapsulated within a polymeric micelle to obtain a water-stable Im@NP nanoparticle for in vivo applications. After intravenous administration to 4T1 tumor-bearing BALB/c mice, Im@NP demonstrated highly efficient imaging-guided PDT ablation of implanted tumors. This is because the delivered (ER)PSIm cargos of Im@NP are specifically activated in the hypoxic microenvironment of solid tumor, and the activated (PS)-P-ER molecules have efficient ER-targeted type-I photosensitivity.