Surface-Engineered Extracellular Vesicles in Cancer Immunotherapy

Abstract

Extracellular vesicles (EVs) are lipid bilayer-enclosed bodies secreted by all cell types. EVs carry bioactive materials, such as proteins, lipids, metabolites, and nucleic acids, to communicate and elicit functional alterations and phenotypic changes in the counterpart stromal cells. In cancer, cells secrete EVs to shape a tumor-promoting niche. Tumor-secreted EVs mediate communications with immune cells that determine the fate of anti-tumor therapeutic effectiveness. Surface engineering of EVs has emerged as a promising tool for the modulation of tumor microenvironments for cancer immunotherapy. Modification of EVs' surface with various molecules, such as antibodies, peptides, and proteins, can enhance their targeting specificity, immunogenicity, biodistribution, and pharmacokinetics. The diverse approaches sought for engineering EV surfaces can be categorized as physical, chemical, and genetic engineering strategies. The choice of method depends on the specific application and desired outcome. Each has its advantages and disadvantages. This review lends a bird's-eye view of the recent progress in these approaches with respect to their rational implications in the immunomodulation of tumor microenvironments (TME) from pro-tumorigenic to anti-tumorigenic ones. The strategies for modulating TME using targeted EVs, their advantages, current limitations, and future directions are discussed.

Keywords: apoptotic bodies; cancer immunotherapy; drug delivery system; exosomes; extracellular vesicles; immunomodulation; microvesicles; surface engineering; tumor immune microenvironment; tumor-secreted EVs.

Figure 2

(a) Schematic representation of the surface-expressed SMART exosomes derived from the Anti-CD3-anti-HER2-engineered Expi293 cells exhibiting a bispecific scFv antibody, targeting breast cancer-associated HER2 receptors and the T-cell CD3. (b) Preparation of SAV-LA-expressing exosomes (SAV-exo). B16BL6 cells were transfected with plasmid DNA encoding streptavidin (SAV) fusion with lactahedrin (LA). SAV-exo were collected from the culture supernant of B16BL6 cells. Further, CpG-SAV-exo were prepared by mixing SAV-exo and biotinylated CpG DNA for enhanced tumor antigen presentation (red arrow). Adapted with permission from Shi et al., 2020 and Morishita et al., 2016 [41,73].

Figure 1

A graphical illustration of extracellular vesicle surface engineering strategies.