Extracellular vesicles as biomarkers and drug delivery systems for tumor

Abstract

Extracellular vesicles (EVs) are crucial for facilitating intercellular communication, promoting cell migration, and orchestrating the immune response. Recently, EVs can diagnose and treat tumors. EVs can be measured as biomarkers to provide information about the type of disease and therapeutic efficacy. Furthermore, EVs with lower immunogenicity and better biocompatibility are natural carriers of chemicals and gene drugs. Herein, we review the molecular composition, biogenesis, and separation methods of EVs. We also highlight the important role of EVs from different origins as biomarkers and drug delivery systems in tumor therapy. Finally, we provide deep insights into how EVs play a role in reversing the immunosuppressive microenvironment.

Keywords: Biomarkers; Drug delivery systems; Drug loading methods; Extracellular vesicles; Molecular composition; Separation technologies; Tumor immunotherapy; Tumor microenvironment.

Graphical abstract

Figure 1

Vesicles derived from the plasma membrane or Golgi apparatus can fuse with early endosomes, and then begin sorting and transport to the extracellular matrix. During this period, early endosomes invaginate, bud and accumulates intraluminal vesicles to form MVBs, and finally fuse with lysosomes. MVBs can release intracellular vesicles by fusing with the plasma membrane, thus producing exosomes.

Figure 2

(A) Schematic representation of ELISA for detecting human exosomal PD-L1. (B) PD-L1 levels on exosomes isolated from plasma samples of nude mice. Reprinted with the permission from Ref. . Copyright © 2018 Springer Nature Limited. (C) Levels of EV-GPX3 and EV-ACTR3 and corresponding protein expression in patients before SIRT + sorafenib treatment. (D) Abundance and (E) Percent survival of EV-ARHGAP1 and EV-GPX3. Reprinted with the permission from Ref. . Copyright © 2022 American Association for Cancer Research. (F) Western blot analysis of the astrocyte-specific EVs for the ITGB1 in the M7/astrocyte-EV module. (G) Western blot semiquantitative analysis plots. Reproduced with permission from Ref. . Copyright © 2021 The Authors.

Figure 3

(A) Scheme of biogenesis and isolation of faeces-derived EVs. (B) The expression levels of CD147 and A33. Reproduced with permission from Ref. . Copyright © 2023 Zhang et al. (C) Mechanism of circSHKBP1 regulating the progression of GC. (D) Migration and invasion of BGC823 and HGC27 cells. Reproduced with permission from Ref. . Copyright © 2020 Xie et al. (E) Scatter plot of CA19-9, GPC1 Exo-mRNA and tMV-mProtein expression. Reproduced with permission from Ref. . Copyright © 2023 Li et al. (F) ROC curves for PDAC stage I/II and III/IV patients. Reproduced with permission from Ref. . Copyright 2023 Li et al.

Figure 4

(A) TDEVs enhance anti-tumor immune response. (B) TDEVs inhibit anti-tumor immune response.

Figure 5

(A) TDEVs activate immune response by promoting T cell expansion. (B) MSC-EVs inhibits tumor cell growth through miRNA-mediated mechanisms. (C) DC-EVs stimulate immune activation by promoting T cell expansion directly. (D) M1-EVs polarize TAMs from the M2 phenotype to the M1 phenotype, thus reversing the TME.

Figure 6

(A) Scheme diagram of engineered EVs derived from M2 macrophages for tospinal cord injury therapy. Reproduced with permission from Ref. . Copyright © 2021 The Author(s). (B) Proportion of fluorescence intensity and wound size of skin wounds extracted from different treatments. Reproduced with permission from Ref. . Copyright © 2023 American Chemical Society. (C) M2-EVs down-regulate MISP levels, up-regulate IQGAP1 levels and then phosphorylated STAT3 and promote PD-L1 transcript expression. Reproduced with permission from Ref. . Copyright © 2023 Elsevier B.V. (D–F) Flow cytometry analysis of phenotypes of macrophages. Reproduced with permission from Ref. . Copyright © 2022 Wiley-VCH GmbH. (E) Schematic diagram of macrophage polarization. Reproduced with permission from Ref. . Copyright © 2022, Wiley-VCH GmbH.

Figure 7

(A) Common methods of pre-loading. (B) Common methods of post-loading.

Figure 8

(A) Scheme of dual-targeted therapeutic EVs containing high copy numbers of TP53 mRNA and siKRASG12D. Reproduced with permission from Ref. . Copyright © 2023 Springer Nature Limited. (B) Compared to stEVs or LNPs, dtEVs penetrate deeper into the tumor spheroids of PANC-1 cells. Reproduced with permission from Ref. . Copyright © 2023 Springer Nature Limited. (C) CD8 and nuclear immunostaining on brain tumor sections. Reproduced with permission from Ref. . Copyright © 2023 The Authors. (D) Analysis of the assessment of IL-12 expression. (E) Flow cytometry analysis of immune cells infiltrating lung tumors after 3 days of treatment. Reproduced with permission from Ref. . Copyright © 2024 Springer Nature Limited.

Figure 9

(A) The therapeutic mechanism of CpG-EXO/TGM. Reprinted with the permission from Ref. . Copyright © 2023 American Chemical Society. (B) Schematic depiction of Rg3-Exo/ATO@Ce6-mediated highly potent and orthotopic GBM-specific synergistic therapy. Reprinted with the permission from Ref. . Copyright © 2023 Elsevier B.V. (C) Mechanism diagram of personalized nanovaccine Dex-HDL/ALA-Fe₃O₄ enhancing lymph node aggregation and reprogramming tumor microenvironment. Reprinted with the permission from Ref. . Copyright © 2024 American Chemical Society.