The therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O concentration. Based on this, a new living drug delivery system integrated PDT and hypoxia-triggered gene therapy is proposed, which is made up of three primary constituents: hypoxia-induced cleaved azobenzene (Azo) bridges, HIF-1α-against antisense oligonucleotide (ASO)/G4-constituted double-stranded DNA/RNA hybridization complex (DRHC) and the photosensitizer TMPyP4. During PDT, the continuous consumption of oxygen could remarkably facilitate an intracellular low-oxygen microenvironment. Then, the hypoxia-responsive Azo bridges were reduced by the highly expressed reductases to amines under the oxygen-deficient environment, resulting in a hypoxia-triggered ASO release and providing a synergistic therapy with PDT for suppression of tumor growth. This new drug delivery system opens a new avenue for the design and fabrication of smart drug delivery methods, which can deliver and release drugs according to the specific biological microenvironment in the body.