Photodynamic　therapy,　during　which　nontoxic　photosensitizers　can　be　photo-activated　to　generate　cytotoxic　reactive　oxygen　species,　has　attracted　great　interest.　However,　the　strong　aggregation　and　poor　tumor　targeting　of　photosensitizers,　the　short　action　radius　and　lifetime　of　reactive　oxygen　species　limit　the　therapeutic　efficiency　greatly.　Herein,　indomethacin,　an　inhibitor　and　substrate　of　cyclooxygenase-2,　is　introduced　to　conjugate　with　zinc　phthalocyanines　for　successively　solving　these　three　problems.　Own　to　indomethacin　moiety,　our　designed　photosensitizer　IMC-Pc　can　bind　to　cyclooxygenase-2　with　reduced　aggregation,　and　its　binding　mechanism　was　demonstrated　by　fluorescence　enhancement　and　docking　calculations.　Subsequently,　the　indomethacin　moiety　assists　ZnPc　selectively　targeting　to　cyclooxygenase-2　expressive　tumor　cells,　and　further　accumulating　in　Golgi　apparatus.　Importantly,　our　results　exhibit　the　improved　intracellular　reactive　oxygen　species　generation　and　enhanced　anticancer　efficacy　of　IMC-Pc.　Overall,　such　a　novel　photosensitizer　with　＇three-in-one＇　cyclooxygenase-2-driven　dual　targeting　and　aggregation　inhibition　is　a　promising　candidate　for　improving　therapeutic　efficacy.　©　2021