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Engineered Nanovaccine Targeting Clec9a+ Dendritic Cells Remarkably Enhances the Cancer Immunotherapy Effects of STING Agonist

  • Shanshan Gou
    Shanshan Gou
    School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
    More by Shanshan Gou
  • Wenwen Liu
    Wenwen Liu
    School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
    More by Wenwen Liu
  • Shuai Wang
    Shuai Wang
    School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
    More by Shuai Wang
  • Guanyu Chen
    Guanyu Chen
    School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
    More by Guanyu Chen
  • Zhenzhen Chen
    Zhenzhen Chen
    School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
    Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China
    International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, China
  • Lu Qiu
    Lu Qiu
    School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
    Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China
    International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, China
    More by Lu Qiu
  • Xiuman Zhou
    Xiuman Zhou
    School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
    More by Xiuman Zhou
  • Yahong Wu
    Yahong Wu
    School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
    Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China
    International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, China
    More by Yahong Wu
  • Yuanming Qi
    Yuanming Qi
    School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
    Henan Key Laboratory of Bioactive Macromolecules, Zhengzhou University, Zhengzhou 450001, China
    International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou 450001, China
    More by Yuanming Qi
  • , and 
  • Yanfeng Gao*
    Yanfeng Gao
    School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
    *Phone: +86 020 84723750. Fax: +86 020 84723750. Email: [email protected]
    More by Yanfeng Gao
Cite this: Nano Lett. 2021, 21, 23, 9939–9950
Publication Date (Web):November 15, 2021
https://doi.org/10.1021/acs.nanolett.1c03243
Copyright © 2021 American Chemical Society
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Abstract

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Agonists of the stimulator of interferon gene (STING) are considered as promising therapeutics for cancer immunotherapy. However, drug-delivery barriers and adverse effects limit the clinical application of STING agonists. Therefore, it is an urgent need to develop an ideal delivery system to deliver STING agonists and avoid side effects. Here, we discovered that STING agonists significantly stimulated type I interferon (IFN) secretion in Clec9a+ dendritic cells (DCs). Then, we designed an engineered peptide-expressed biomimetic cancer cell membrane (EPBM)-coated nanovaccine drug-delivery system (PLGA/[email protected]) to deliver STING agonists and tumor antigens to Clec9a+ DCs. The PLGA/[email protected] nanovaccine significantly enhanced IFN-stimulated expression of genes and antigen cross-presentation of Clec9a+ DCs, thus eliciting strong antitumor effects in both anti-PD-1-responsive and -resistant tumor models without obvious cytotoxicity. Moreover, the PLGA/[email protected] nanovaccine combined with radiotherapy exhibited remarkable synergistic antitumor effects. Our work highlights the great potential of a EPBM-coated nanovaccine for systemic STING agonist delivery as an attractive tool for cancer immunotherapy.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.nanolett.1c03243.

  • Materials, mice, and experimental section including the expression of CBP-12, preparation of NPs, cell experiments, and animal experiments; the expression of Clec9a on FL-DCs; interferon-stimulated genes activation and antigen-specific CD8+ T cells priming were determined after B16-OVA and Clec9a+ DCs incubation with STING agonist; CBP-12 was expressed on 4T1 and TC1 cell membrane; cellular uptake of PLGA/[email protected] by Clec9a+ DCs; PLGA/[email protected] nanovaccine could target Clec9a+ DCs in vivo; PLGA/[email protected] could stimulate Clec9a+ DCs to secrete IL-21 in vitro; toxicity evaluation of NPs in vivo; cell viability of B16-OVA cells with different concentrations of NPs; changes in body weight of the B16-OVA tumor-bearing mice over time; the flow cytometry representative graph of Figure 4; ratio of infiltrating DCs in the tumor; ratio of infiltrating Clec9a+ DCs in the tumor after radiotherapy (PDF)

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Cited By


This article is cited by 1 publications.

  1. Kyle M. Garland, Taylor L. Sheehy, John T. Wilson. Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy. Chemical Reviews 2022, 122 (6) , 5977-6039. https://doi.org/10.1021/acs.chemrev.1c00750

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