Photodynamic therapy (PDT) is a promising cancer treatment with minimal invasiveness and high selectivity, but its efficacy depends heavily on subcellular reactive oxygen species (ROS) localization. Although organelle-targeted PDT can enhance antitumor effects, systematic evaluation and comparison of their photocytotoxicity, and photoimmunological activation capacity remain lacking. Herein, we synthesized four organelle-targeted photosensitizers (PSs) using pyropheophorbide a (Ppa) as the core scaffold: Ppa-Mit, Ppa-Lys, Ppa-ER, and Ppa-Nuc, which target mitochondria, lysosomes, endoplasmic reticulum (ER), and nucleus, respectively. These PSs were then individually encapsulated into synthetic high-density lipoprotein (sHDL) nanodiscs to yield PMN, PLN, PEN, and PNN. All nanodiscs achieved specific organelle targeting. Photocytotoxicity followed the order PLN > PMN > PNN > PEN, while PMN exhibited the optimal immunogenic cell death (ICD)-inducing capacity by triggering robust secretion of damage-associated molecular patterns (DAMPs). In vivo, PMN and PLN achieved complete, recurrence-free tumor ablation, promoting infiltration of mature dendritic cells, and cytotoxic CD8+ T cells (expressing Granzyme B) to elicit strong antitumor immunity. This study identifies PMN and PLN as promising PDT agents and highlights mitochondria-targeted and lysosome-targeted PDT as a favorable approach for effective tumor photoimmunotherapy, providing guidance for the rational design of targeted PSs.
| [1] |
Y. Y. Zhao, L. Lu, H. Jeong, et al., “Enhancing Biosafety in Photodynamic Therapy: Progress and Perspectives,” Chemical Society Reviews 54 (2025): 7749-7768.
|
| [2] |
M. Kolarikova, B. Hosikova, H. Dilenko, et al., “Photodynamic Therapy: Innovative Approaches for Antibacterial and Anticancer Treatments,” Medicinal Research Reviews 43 (2023): 717-774.
|
| [3] |
J. Karges, “Clinical Development of Metal Complexes as Photosensitizers for Photodynamic Therapy of Cancer,” Angewandte Chemie International Edition 61 (2022): e202112236.
|
| [4] |
J. Alhoussein, K. Merabishvili, T. Ho, et al., “Next Generation of Porphysomes for Improved Photodynamic Therapy Applications,” Journal of Controlled Release 381 (2025): 113621.
|
| [5] |
S. S. Lucky, K. C. Soo, and Y. Zhang, “Nanoparticles in Photodynamic Therapy,” Chemical Reviews 115 (2015): 1990-2042.
|
| [6] |
M. Niedre, M. S. Patterson, and B. C. Wilson, “Direct Near-Infrared Luminescence Detection of Singlet Oxygen Generated by Photodynamic Therapy in Cells In Vitro and Tissues in Vivo,” Photochemistry and Photobiology 75 (2002): 382-391.
|
| [7] |
K. F. Ferri and G. Kroemer, “Organelle-Specific Initiation of Cell Death Pathways,” Nature Cell Biology 3 (2001): E255-E263.
|
| [8] |
Y. Li, W. Han, D. Gong, et al., “A Self-Assembled Nanophotosensitizer Targets Lysosomes and Induces Lysosomal Membrane Permeabilization to Enhance Photodynamic Therapy,” Chemical Science 14 (2023): 5106-5115.
|
| [9] |
S. Wang, L. Gai, Y. Chen, X. Ji, H. Lu, and Z. Guo, “Mitochondria-Targeted BODIPY Dyes for Small Molecule Recognition, Bio-Imaging and Photodynamic Therapy,” Chemical Society Reviews 53 (2024): 3976-4019.
|
| [10] |
S. Diao, X. He, Y. Wu, et al., “Endoplasmic Reticulum-Targeting Activatable Nanophotosensitizers for Hypoxia Relief and Enhanced Photodynamic Therapy,” Chemical Science 16 (2025): 10909-10917.
|
| [11] |
L. Guo, X. Cao, X. Li, J. Xu, X. Zhao, and H. Lu, “Nucleus and Mitochondria Double-Targeted Phototherapeutic Agent Based on Conjugated Small Molecule for Cancer Cell-Targeted Synergistic Phototherapy,” Sensors and Actuators B: Chemical 418 (2024): 136227.
|
| [12] |
Z.-C. Hu, B. Wang, X.-G. Zhou, et al., “Golgi Apparatus-Targeted Photodynamic Therapy for Enhancing Tumor Immunogenicity by Eliciting NLRP3 Protein-Dependent Pyroptosis,” ACS Nano 17 (2023): 21153-21169.
|
| [13] |
Q. Li, S. Feng, and G. Feng, “A Cell Membrane-Targeted Photosensitizer for Cancer Photodynamic Therapy and Dynamic Ablation Process Tracking,” Sensors and Actuators B: Chemical 422 (2025): 136629.
|
| [14] |
R. Wang, X. Li, and J. Yoon, “Organelle-Targeted Photosensitizers for Precision Photodynamic Therapy,” ACS Applied Materials & Interfaces 13 (2021): 19543-19571.
|
| [15] |
D. Wei, J. Qi, M. R. Hamblin, X. Wen, X. Jiang, and H. Yang, “Near-Infrared Photoimmunotherapy: Design and Potential Applications for Cancer Treatment and Beyond,” Theranostics 12 (2022): 7108-7131.
|
| [16] |
L. Liu, Y. Pan, L. Ye, et al., “Optical Functional Nanomaterials for Cancer Photoimmunotherapy,” Coordination Chemistry Reviews 517 (2024): 216006.
|
| [17] |
X. Yu, L. Zeng, X. Yang, et al., “An NIR-II Absorbing Injectable Hydrogel for Boosted Photo-Immunotherapy Toward Human Papillomavirus Associated Cancer,” Aggregate 6 (2025): e743.
|
| [18] |
S. Zeng, C. Chen, L. Zhang, et al., “Activation of Pyroptosis by Specific Organelle-Targeting Photodynamic Therapy to Amplify Immunogenic Cell Death for Anti-Tumor Immunotherapy,” Bioactive Materials 25 (2023): 580-593.
|
| [19] |
X. Zhao, X. Wu, R. Shang, H. Chen, and N. Tan, “A Structure-Guided Strategy to Design Golgi Apparatus-Targeted Type-I/II Aggregation-Induced Emission Photosensitizers for Efficient Photodynamic Therapy,” Acta Biomaterialia 183 (2024): 235-251.
|
| [20] |
X. Wu, J.-J. Hu, and J. Yoon, “Cell Membrane as a Promising Therapeutic Target: from Materials Design to Biomedical Applications,” Angewandte Chemie International Edition 63 (2024): e202400249.
|
| [21] |
Y. Xu, W. Zeng, R. Liu, Z. Dai, and D. Sun, “Synergistic Nucleus-Targeting Photodynamic Therapy and DNA Repair Inhibition to Activate Innate and Adaptive Antitumor Immunity for Amplifying Photoimmunotherapy,” Nano Letters 25 (2025): 16154-16161.
|
| [22] |
R. Chen, J. Zou, J. Liu, R. Kang, and D. Tang, “DAMPs in the Immunogenicity of Cell Death,” Molecular Cell 85 (2025): 3874-3889.
|
| [23] |
W. Li, J. Yang, L. Luo, et al., “Targeting Photodynamic and Photothermal Therapy to the Endoplasmic Reticulum Enhances Immunogenic Cancer Cell Death,” Nature Communications 10 (2019): 3349.
|
| [24] |
S. Z. Wang, Y. Guo, X. Zhang, et al., “Mitochondria-Targeted Photodynamic and Mild-Temperature Photothermal Therapy for Realizing Enhanced Immunogenic Cancer Cell Death via Mitochondrial Stress,” Advanced Functional Materials 33 (2023): 2303328.
|
| [25] |
K.-H. Li, H.-Y. Zhao, D.-D. Wang, et al., “Mitochondria-Targeted Nano-AIEgens as a Powerful Inducer for Evoking Immunogenic Cell Death,” Chinese Chemical Letters 35 (2024): 108882.
|
| [26] |
Y. Xing, J. Yang, A. Peng, et al., “Lysosome Targeted Nanoparticle Aggregation Reverses Immunosuppressive Tumor Microenvironment for Cancer Immunotherapy,” Advanced Materials 36 (2024): 2412730.
|
| [27] |
Z. Chen, Y. Wang, Z. Li, et al., “Improving Ferroptosis-Mediated Immunotherapy for Colorectal Cancer Through Lysosome-Targeted Photodynamic Therapy,” Materials Today Bio 31 (2025): 101552.
|
| [28] |
Y. Xu, R. Liu, R. Li, et al., “Manipulating Neovasculature-Targeting Capability of Biomimetic Nanodiscs for Synergistic Photoactivatable Tumor Infarction and Chemotherapy,” ACS Nano 17 (2023): 16192-16203.
|
| [29] |
C. Silva-Vilches, S. Ring, and K. Mahnke, “ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity,” Frontiers in Immunology 9 (2018): 417046.
|
| [30] |
T. Yamazaki, D. Hannani, V. Poirier-Colame, et al., “Defective Immunogenic Cell Death of HMGB1-Deficient Tumors: Compensatory Therapy With TLR4 Agonists,” Cell Death & Differentiation 21 (2014): 69-78.
|
| [31] |
A. Murshid, J. Gong, and S. K. Calderwood, “The Role of Heat Shock Proteins in Antigen Cross Presentation,” Frontiers in Immunology 3 (2012): 63.
|
RIGHTS & PERMISSIONS
2026 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.
PDF
(6326KB)
