An Active Self-Mitochondria-Targeting Cyanine Immunomodulator for Near-Infrared II Fluorescence Imaging-Guided Synergistic Photodynamic Immunotherapy

Photodynamic therapy (PDT) targeting mitochondria represents a promising therapeutic strategy for fighting diverse types of cancers. However, the currently available photosensitizers (PSs) suffer from insufficient therapeutic potency, limited mitochondria delivery efficiency, and the inability to treat invisible metastatic distal cancers. Herein, an active self-mitochondria-targeting heptapeptide cyanine (HCy) immunomodulator (I 2 HCy-QAP) is reported for near-infrared II (NIR-II) fluorescence imaging-guided photodynamic immunotherapy of primary and distal metastatic cancers. The I 2 HCy-QAP is designed by introducing a quaternary ammonium salt with a phenethylamine skeleton (QAP) into the iodinated HCy photosensitizer. The I 2 HCy-QAP can precisely target mitochondria due to the lipophilic cationic QAP unit, present strong NIR-II fluorescence tail emission, and effectively generate singlet oxygen 1 O 2 under NIR laser irradiation, thereby inducing mitochondria-targeted damages and eliciting strong systemic immunogenic cell death immune responses. The combination of the I 2 HCy-QAP-mediated photodynamic immunotherapy with anti-programmed death-1 antibody therapy achieves remarkable therapeutic efficacy against both primary and distal metastatic cancers with significant inhibition of lung metastasis in a triple-negative breast cancer model. This work provides a new concept for designing high-performance NIR emissive cyanine immunomodulators for NIR-II fluorescence-guided photodynamic immunotherapy. This article is protected by copyright. All rights reserved