Mitochondria-Targeting and Multiresponsive Nanoplatform Based on AIEgens for Synergistic Chemo-Photodynamic Therapy and Enhanced Immunotherapy

Although photodynamic therapy (PDT) has become an attractive strategy for cancer treatment, its clinical application still suffers from some limitations, including insufficient delivery of photosensitizers, hypoxic tumor environment, and the development of PDT resistance. To address these limitations, a new class of mitochondria-targeting and fluorinated polymer with aggregation-induced emission characteristics was fabricated to sensitize PDT and co-deliver chemotherapeutic drugs. The amphiphilic fluoropolymer was able to efficiently carry oxygen and SN-38 (the active metabolite of irinotecan) and self-assemble into multifunctional micellar nanoparticles (SN-38-TTCF@O₂ NPs). Upon internalization into tumor cells, these NPs could successfully escape lysosomes, selectively target mitochondria, efficiently produce reactive oxygen species (ROS) under light irradiation, and release drugs in response to ROS. In the HCT116 tumor xenograft model, they preferentially accumulated in tumor tissue and significantly alleviated tumor hypoxia, resulting in synergistic chemo-PDT efficacy without distinct toxicity. Furthermore, the nanoscale chemo-PDT induced immunogenic cell death, promoted the recruitment and activation of cytotoxic T lymphocytes, and ultimately augmented the anti-tumor efficacy of anti-PD-1 antibody in the murine CT26 tumor model. These results may provide novel insights into the development of efficient chemo-PDT nanomedicine to improve the outcome of immunotherapy.