4.8 Article

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

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 2, Pages 787-797

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c09753

Keywords

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Funding

  1. National Natural Science Foundation of China (NSFC) [32171318, 32101069]
  2. Faculty of Health Sciences, University of Macau
  3. University of Macau [SRG2018-00130-FHS]
  4. Science and Technology Development Fund, Macau SAR [0109/2018/A3, 0011/2019/AKP, 0113/2019/A2, 0103/2021/A]
  5. Shenzhen Science and Technology Innovation Commission, Shenzhen-Hong Kong-Macau Science and Technology Plan C [SGDX20201103093600004]
  6. Proteomics, Metabolomics and Drug Development Core in the Faculty of Health Sciences, University of Macau
  7. Animal Research Core in the Faculty of Health Sciences, University of Macau
  8. Biological Imaging and Stem Cell Core in the Faculty of Health Sciences, University of Macau

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In this study, phototheranostic metal-phenolic networks were engineered for precise photo thermal therapy. This therapy could relieve exosomal suppression, restore T cells, and enhance ferroptosis. The synergy of photo thermal therapy with antiexosomal PD-L1 evoked potent antitumor immunity and immunological memory against metastatic tumors.
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-Ll 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 photo thermal 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.

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