Development of DNA-anchored assembly of small extracellular vesicle for efficient antigen delivery to antigen presenting cells

Biomaterials. 2019 Dec:225:119518. doi: 10.1016/j.biomaterials.2019.119518. Epub 2019 Sep 25.

Abstract

Tumor-cell derived small extracellular vesicle (sEV) combined with immunostimulatory adjuvants may serve as a promising tumor vaccine through the induction of the cytotoxic T cell response. To achieve an efficient immune response, the prolonged tissue residence after intradermal injection followed by the sustained and efficient delivery of tumor-cell derived sEV combined with adjuvants to antigen-presenting cells (APCs) is a promising strategy. In the present study, we constructed a DNA-anchored sEV superstructure in which tumor-cell derived sEVs were assembled with each other to achieve prolonged tissue residence and the ability to encourage selective uptake by dendritic cells. We prepared sEVs modified with immunostimulatory CpG-DNA containing an additional "sticky end" (CpG-sEV). CpG-sEVs were mixed with an oligonucleotide duplex containing the sequence complementary to the "sticky end" of the CpG-DNA, resulting in the self-assembly of CpG-sEV into a micrometer-sized superstructure. The CpG-DNA anchored sEV assembly (CpG-sEV assembly) was selectively taken up by APCs, compared to tumor cells or fibroblast cells, and it efficiently activated dendritic cells in vitro. Moreover, CpG-sEV assembly formation significantly prolonged tissue residence and increased the immune responses of immunostimulatory CpG-DNA intradermally injected into mice. These results indicate that CpG-sEV assembly is an effective system which may be useful for tumor immunotherapy.

Keywords: Antigen presenting cell (APC); Assembly; CpG-DNA; DNA nanotechnology; Immunotherapy; Small extracellular vesicle (sEV).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / metabolism*
  • Antigens / administration & dosage*
  • Cytokines / metabolism
  • DNA / metabolism*
  • Endocytosis / drug effects
  • Extracellular Vesicles / metabolism*
  • Immunomodulation / drug effects
  • Injections, Intradermal
  • Male
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice, Inbred C57BL
  • Oligodeoxyribonucleotides / pharmacology

Substances

  • Antigens
  • CPG-oligonucleotide
  • Cytokines
  • Oligodeoxyribonucleotides
  • DNA