Phototheranostic Metal-Phenolic Networks with Antiexosomal PD-L1 Enhanced Ferroptosis for Synergistic Immunotherapy

• Published in: Journal of the American Chemical Society Vol. 144; no. 2; pp. 787 - 797
• Main Authors: Xie, Lisi, Li, Jie, Wang, Guohao, Sang, Wei, Xu, Mengze, Li, Wenxi, Yan, Jie, Li, Bei, Zhang, Zhan, Zhao, Qi, Yuan, Zhen, Fan, Quli, Dai, Yunlu
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 19.01.2022
• Subjects: Aniline Compounds - chemistry; Animals; B7-H1 Antigen - metabolism; Benzylidene Compounds - chemistry; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Exosomes - metabolism; Ferric Compounds - chemistry; Ferroptosis - drug effects; Immunogenic Cell Death - drug effects; Immunotherapy; Interferon-gamma - metabolism; Melanoma, Experimental - diagnostic imaging; Melanoma, Experimental - therapy; Metal-Organic Frameworks - chemistry; Metal-Organic Frameworks - pharmacology; Metal-Organic Frameworks - therapeutic use; Mice; Phenol - chemistry; Photoacoustic Techniques; Polyethylene Glycols - chemistry; Polymers - chemistry; Programmed Cell Death 1 Receptor - metabolism; Theranostic Nanomedicine
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.1c09753

Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe3+) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.