Molecular engineering strategies for fabricating type-I mitochondria-targeted aggregation-induced emission photosensitizers for apoptosis-ferroptosis synergistically boosting photodynamic therapy

The precise distribution and subcellular localization of photosensitizers (PSs) play a crucial role in maximizing the utilization of reactive oxygen species (ROS) and enhancing photodynamic therapy (PDT). However, the therapeutic efficacy of PDT is significantly compromised by the hypoxic microenvironment, particularly in malignant tumors. To address these challenges, we designed and synthesized three donor–donor-π-bridge-acceptor (D-D-π-A) type aggregation-induced emission (AIE) PSs: TCM-OTs , TCM-OH , and TCPy-OH . By fine-tuning the acceptor and donor substituents, we successfully modulated organelle-targeting specificity and ROS generation to mitigate hypoxia-related limitations. Among these compounds, TCM-OH emerged as a highly promising PS, exhibiting selective mitochondrial targeting and efficient type-I ROS generation. To further enhance its pharmacological properties, we encapsulated each PS into DSPE-PEG2k to form nanoparticles (NPs). Notably, TCM-OH NPs facilitated the production of superoxide (•O 2 − ) and hydroxyl radicals (•OH) within mitochondria, leading to mitochondrial dysfunction and subsequent cell death via a synergistic ferroptosis-apoptosis pathway under light irradiation. Both in vitro and in vivo experiments demonstrated the potent therapeutic efficacy of this strategy, with minimal toxicity, underscoring its potential for hypoxic cancer treatment. Overall, this study provides a rational design framework for developing potent type-I PSs with multimodal capabilities for biomedical applications.