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Research Article

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

Zhan Shi1,2,§, Xue Wang1,2,§, Jiali Luo1,2, Yiqing Zeng1,2, Qing Wen1,2, Yurong Hong1,2, Tao Zhang1,2( ), Pintong Huang1,2,3( )
Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310009, China

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

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Graphical Abstract

The functional lipid droplets (LDs) (CPI-613/IR780@LDs) synergistically inhibited the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) to increase reactive oxygen species (ROS) generation at the tumor site, thus enhancing the efficacy of mitochondria-targeted sonodynamic therapy (SDT) in hypoxic pancreatic cancer. Moreover, the combination of CPI-613/IR780@LD-mediated mitochondria-targeted SDT and anti-PD-1 antibody exhibited excellent tumor inhibition and activated anti-tumor immune responses.

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 developing 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.

Keywords

hypoxiapancreatic cancerlipid dropletmitochondria-targeted sonodynamic therapyimmunotherapy

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Nano Research
Volume 16 Issue 5,
May 2023
Pages 7187-7198
DOI: 10.1007/s12274-022-5340-0
Cite this article:
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 Research, 2023, 16(5): 7187-7198. https://doi.org/10.1007/s12274-022-5340-0
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Received: 19 October 2022
Revised: 16 November 2022
Accepted: 17 November 2022
Published: 10 January 2023
© Tsinghua University Press 2022
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