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T7 peptide-decorated exosome-based nanocarrier system for delivery of Galectin-9 siRNA to stimulate macrophage repolarization in glioblastoma

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Abstract

Purpose

Exosomes are nano-vesicular carriers capable of delivering cargoes for intercellular communication, which holds potential as biocompatible and high efficiency systems for drug delivery. In this study, we evaluated the potential effect of T7 peptide-decorated exosome-loaded Galectin-9 siRNA (T7-Exo/siGalectin-9) in the M1 polarization of macrophages and immunosuppression of glioblastoma (GBM).

Methods

Differentially expressed genes in GBM were in silico predicted and then experimentally verified. Galectin-9 was knocked down by siRNA to assess its role in tumor-bearing mice. T7 peptide-decorated exosomes (derived from human embryonic kidney [HEK]-293T cells) targeting GBM were prepared, and loaded with Galectin-9 siRNA by electroporation to prepare nanoformulations (T7-Exo/siGalectin-9). The role of T7-Exo/siGalectin-9 in CD8+ T cell cytotoxicity to target GBM cells and polarization of macrophages was evaluated after artificial modulation of Galectin-9 expression. Anti-tumor effects of T7-Exo/siGalectin-9 were elucidated in vitro and in vivo.

Results

Galectin-9 was highly expressed in GBM tissues and cell lines. The siRNA-mediated knockdown of Galectin-9 repressed the growth of xenografts of GBM cells in C57BL/6 mice and activated immune response in the tumor microenvironment. T7-Exo/siGalectin-9 effectively delivered siGalectin-9 to GBM cells. T7-Exo/siGalectin-9 contributed to activation of the TLR7-IRF5 pathway, which polarized macrophages to M1 phenotype. By this mechanism, phagocytosis of GBM cells by macrophages was increased, the anti-tumor effect of CD8+ T cells was enhanced and the inflammatory responses were suppressed.

Conclusion

Overall, T7-Exo/siGalectin-9 promotes macrophage repolarization and restricts the immunosuppression of GBM, thus providing novel insights into and drug delivery system of immunotherapy for GBM.

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Data availability

The datasets generated/analyzed during the current study are available.

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, People’s Republic of China

    Chenguang Li & Ning Guan

  2. Department of Anesthesiology, The First Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Renmin Street, Jinzhou, 121000, Liaoning, People’s Republic of China

    Feifei Liu

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Contributions

CL, NG and FL designed the study. CL, NG and FL collated the data, designed and developed the database, carried out data analyses and produced the initial draft of the manuscript. CL, NG and FL contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Feifei Liu.

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Supplementary Information

11060_2023_4257_MOESM1_ESM.eps

Figure S1 Flow cytometric analysis of macrophage polarization in TILs (A, for panel 1I), IFN-γ+ CD8+ T cell percentage in TILs (B, for panel 1J), and IFN-γ+ CD8+ T cells treated with Galectin-9 alone or combined with oe-IRF5/oe-TLR7 (C, for panel 5C) (EPS 2444 KB)

11060_2023_4257_MOESM2_ESM.eps

Figure S2 Detection of the effect of electroporation on exosomes. A, The protein expression of CD63, CD9, and CD81 in T7-Exos and T7-Exo/siGalectin-9 detected by Western blot analysis. B, Observation of T7-Exos and T7-Exo/siGalectin-9 by TEM. C, The size of T7-Exos and T7-Exo/siGalectin-9 (EPS 7485 KB)

11060_2023_4257_MOESM3_ESM.eps

Figure S3 Flow cytometric analysis of CD68+ cells in THP-1 cells stimulated by PMA (A, for panel 4D), as well as CD11b+, CD206+, CD11b+ and CD80+ cells (B and C, for panel 4G) and CFSE+ eFluor®670+ cells (D, for panel 4I) after Galectin-9 supplement alone or combined with oe-IRF5/oe-TLR7 (EPS 3567 KB)

Supplementary Table S1 (DOCX 19 KB)

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Li, C., Guan, N. & Liu, F. T7 peptide-decorated exosome-based nanocarrier system for delivery of Galectin-9 siRNA to stimulate macrophage repolarization in glioblastoma. J Neurooncol 162, 93–108 (2023). https://doi.org/10.1007/s11060-023-04257-y

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