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RNA sequencing-based optimization of biological lipid droplets for sonodynamic therapy to reverse tumor hypoxia and elicit robust immune response

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Abstract

Mitochondria-targeted sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate the anti-tumor immune responses. Identifying the mechanisms underlying mitochondria-targeted SDT, further optimizing its efficacy, and develo** novel sonosensitizer carriers with good biocompatibility pose major challenges to the clinical practice of SDT. In this study, we investigated the mechanisms of mitochondria-targeted SDT and demonstrated that it suppressed the mitochondrial electron transport chain (ETC) in pancreatic cancer cells through RNA-sequencing analysis. Based on these findings, we constructed the functional lipid droplets (LDs) (CPI-613/IR780@LDs), which combined mitochondria-targeted SDT with the tricarboxylic acid (TCA) cycle inhibitor CPI-613. CPI-613/IR780@LDs synergistically inhibited the TCA cycle and the ETC of mitochondrial aerobic respiration to reduce oxygen consumption and increase reactive oxygen species (ROS) generation at the tumor site, thus enhancing the efficacy of SDT in hypoxic pancreatic cancer. Moreover, the combination of mitochondria-targeted SDT and anti-PD-1 antibody exhibited excellent tumor inhibition and activated anti-tumor immune responses by increasing tumor-infiltrating CD8+ T cells and reducing regulatory T cells, synergistically arresting the growth of both primary and metastatic pancreatic tumors. Meanwhile, lipid droplets are cell-derived biological carriers with natural mitochondrial targeting ability and can achieve efficient hydrophobic drug loading through active phagocytosis. Therefore, the functional lipid droplet-based SDT combined with anti-PD-1 antibody holds great potential in the clinical treatment of hypoxic pancreatic cancer.

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Acknowledgments

We greatly acknowledge the financial support from the National Natural Science Foundation of China (Nos. 32201138, 82030048, and 82230069) and the Key Research and Development Program of Zhejiang Province (No. 2019C03077).

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Author notes

  1. Zhan Shi and Xue Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China

    Zhan Shi, Xue Wang, Jiali Luo, Yiqing Zeng, Qing Wen, Yurong Hong, Tao Zhang & Pintong Huang

  2. Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China

    Zhan Shi, Xue Wang, Jiali Luo, Yiqing Zeng, Qing Wen, Yurong Hong, Tao Zhang & Pintong Huang

  3. Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310009, China

    Pintong Huang

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  1. Zhan Shi
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Correspondence to Tao Zhang or Pintong Huang.

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RNA sequencing-based optimization of biological lipid droplets for sonodynamic therapy to reverse tumor hypoxia and elicit robust immune response

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Shi, Z., Wang, X., Luo, J. et al. RNA sequencing-based optimization of biological lipid droplets for sonodynamic therapy to reverse tumor hypoxia and elicit robust immune response. Nano Res. 16, 7187–7198 (2023). https://doi.org/10.1007/s12274-022-5340-0

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  • DOI: https://doi.org/10.1007/s12274-022-5340-0

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