The less oxygen-dependent, cellular organelle-specific photosensitizers (PSs) with long-term in-vivo imaging and efficient reactive oxygen species (ROS) generation capabilities are highly desirable for imaging-guided photodynamic therapy (PDT) under hypoxia, but still challenging. In this contribution, three mitochondria-targeting, aggregation-induced emission (AIE)-based photosensitizers termed as TPEPyTMB-1 (monomeric), TPEPyTMB-2 (dimeric) and TPEPyTMB-3 (trimeric) were synthesized to enhance the AIE-effect, ROS generation, and mitochondria-targeting ability. The rationally synthesized AIE-PSs efficiently produce a mixture of type-1 and type-2 ROS with excellent photophysical properties in terms of near-infrared (NIR) emission, large Stock-shift (> 225 nm) and high photostability. The biocompatible AIE-PSs nanoparticles (AIE-PSs NPs) were fabricated using an amphiphilic block copolymer (DSPE-PEG). Among them, TPEPyTMB-3 NPs with superior intracellular ROS production efficiency as well as greater mitochondria-targeting capabilities, demonstrated efficient PDT efficacy in both normoxia and hypoxia environments. In-vivo results revealed that TPEPyTMB-3 NPs can effectively inhibit the growth of subcutaneous tumors, under white light irradiation with minimized systemic toxicity. Moreover, TPEPyTMB-3 NPs accumulated at tumor sites and displayed outstanding long-term in-vivo imaging capability (up to 7 days). This study provides a new perspective for developing the emerging AIE-PSs to maximize PDT performance through the trimerization of small AIE-photosensitizer.