Strategically Designed Mitochondria-Targeting AIEgens for Effective Eradication of Primary and Metastatic Tumors via Synergistic Phototherapy and Induced Immunogenic Cell Death

In recent years, photoimmunotherapy has emerged as an innovative modality in antitumor therapy, garnering significant research interest due to its integration of the advantages of both phototherapy and immunotherapy. However, despite extensive efforts to advance photoimmunotherapy, the design strategies for photoimmunotherapy agents remain uncertain, significantly hindering progress in this field. Here, a novel molecular design strategy for developing superb photoimmunotherapy agents that integrates aggregation-induced emission (AIE) activity, mitochondria targeting, high-efficiency reactive oxygen species generation, and high photothermal conversion capabilities into a single molecule is proposed. A comprehensive study demonstrates that the target molecule (TPETTBI) that is strategically designed can exert prominent photodynamic therapy (PDT) and photothermal therapy (PTT) effects, leading to tumor cell death. More importantly, the synergistic action of PDT and PTT can further induce mitochondrial dysfunction and trigger large-scale immunogenic cell death (ICD) to attain a long-lasting effect of antitumor immunity. Therefore, this work provides new insights into the rational design of phototherapy agents for precise and efficient tumor treatment by integrating synergistic PDT, PTT, and ICD-based immunotherapy within a single molecule.