A good photosensitizer (PS) delivery system could enhance the efficiency and reduce the side effects of anti-tumor photodynamic therapy (PDT) by improving accumulation in the tumor, uptake by tumor cells, and intracellular release of the PS. Thus, we rationally developed a multi-stimulus-responsive PS nanocarrier with a double-layered core-shell structure: mPEG-azo-hyaluronic acid-sulfide-Ce6 (PaHAsC). In PaHAsC, the mPEG coat provides protection before entering the hypoxic tumor microenvironment, where mPEG leaves to expose the HA layer. HA then targets overexpressed CD44 on tumor cells for enhanced internalization. Finally, GSH-mediated intracellular release of Ce6 augments ROS generation and O2 consumption under light stimulation. This also aggravates hypoxia in tumor sites to accelerate mPEG removal, forming a positive feedback loop. Data show that PaHAsC dramatically improved the PDT efficacy of Ce6, eliminating most tumors and 80% of tumor-bearing mice survived. With a safe profile, PaHAsC has potential for further development and is a useful example of a PS delivery system.