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Identification of splenic IRF7 as a nanotherapy target for tele-conditioning myocardial reperfusion injury

Author

Listed:
  • Qiang Long

    (Shanghai Jiao Tong University School of Medicine)

  • Kristina Rabi

    (University of Tartu)

  • Yu Cai

    (Xiamen University)

  • Lihui Li

    (Shanghai Jiao Tong University School of Medicine)

  • Shixing Huang

    (Shanghai Jiao Tong University School of Medicine)

  • Bei Qian

    (Shanghai Jiao Tong University School of Medicine)

  • Yiming Zhong

    (Shanghai Jiao Tong University School of Medicine)

  • Zhaoxi Qi

    (Shanghai Jiao Tong University School of Medicine)

  • Yecen Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Kaichen Huang

    (Shanghai Jiao Tong University School of Medicine)

  • Xinming Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Lan Chang

    (Shanghai Jiao Tong University School of Medicine)

  • Weichang Xie

    (Shanghai Jiao Tong University School of Medicine)

  • Huaiyu Jiang

    (Shanghai Jiao Tong University School of Medicine)

  • Haonan Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Junjie Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Ting Ren

    (Shanghai Jiao Tong University School of Medicine)

  • Zichen Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Tambet Teesalu

    (University of Tartu)

  • Caisheng Wu

    (Xiamen University)

  • Lin Lu

    (Shanghai Jiao Tong University School of Medicine)

  • Zhengbin Zhu

    (Shanghai Jiao Tong University School of Medicine)

  • Yiwei Chu

    (Fudan University)

  • Hélder A. Santos

    (University of Helsinki
    University Medical Center Groningen, University of Groningen (UMCG))

  • Zehua Liu

    (University of Helsinki
    University Medical Center Groningen, University of Groningen (UMCG))

  • Qiang Zhao

    (Shanghai Jiao Tong University School of Medicine)

  • Xiaofeng Ye

    (Shanghai Jiao Tong University School of Medicine)

Abstract

The sequestration of nanoparticles by mononuclear phagocyte system is a challenge for the use of nanotherapy for treating cardiovascular diseases due to the conventionally perceived loss of therapeutic potency. Here, we revitalize cardiovascular nanotherapy by unlocking an alternative route in which nanomedicines are redirected to the spleen, leveraging its potential as a highly efficient and targeted site for remote conditioning, or tele-conditioning myocardial reperfusion injury. The theoretical foundation underpinning is the splenogenic nature of recruited monocytes upon myocardial reperfusion in the acute stage, which is confirmed through murine heterotopic spleen transplantation. Single-cell RNA-seq analysis identifies IRF7 as a pivotal mediator in the spleen-heart communication network that is initially induced in the spleen and orchestrates functional changes in myocardial macrophages. Spleen-related induction of IRF7 is also valid in human myocardial reperfusion scenarios. In addition, in a murine preclinical model of male mice, temporal inhibition of splenic IRF7 through the designed spleen-targeting erythrosome engineered with the targeting peptide RP182, termed as STEER nanoparticles, mitigates the acute-stage innate immune responses and improves the cardiac function in the long term. In contrast, systemic inhibition, genetic knockout of IRF7 or absolute depletion of splenic monocytes does not have therapeutic benefits, indicating the superiority of nanoparticle-based targeted treatment. These findings establish the spleen as a naturally favored site for nanoparticle-based treatments, offering promising avenues for managing myocardial reperfusion injury.

Suggested Citation

  • Qiang Long & Kristina Rabi & Yu Cai & Lihui Li & Shixing Huang & Bei Qian & Yiming Zhong & Zhaoxi Qi & Yecen Zhang & Kaichen Huang & Xinming Wang & Lan Chang & Weichang Xie & Huaiyu Jiang & Haonan Zha, 2025. "Identification of splenic IRF7 as a nanotherapy target for tele-conditioning myocardial reperfusion injury," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57048-6
    DOI: 10.1038/s41467-025-57048-6
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    References listed on IDEAS

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    1. Kenya Honda & Hideyuki Yanai & Hideo Negishi & Masataka Asagiri & Mitsuharu Sato & Tatsuaki Mizutani & Naoya Shimada & Yusuke Ohba & Akinori Takaoka & Nobuaki Yoshida & Tadatsugu Taniguchi, 2005. "IRF-7 is the master regulator of type-I interferon-dependent immune responses," Nature, Nature, vol. 434(7034), pages 772-777, April.
    2. Seung-Hyun Jung & Byung-Hee Hwang & Sun Shin & Eun-Hye Park & Sin-Hee Park & Chan Woo Kim & Eunmin Kim & Eunho Choo & Ik Jun Choi & Filip K. Swirski & Kiyuk Chang & Yeun-Jun Chung, 2022. "Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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