A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties

Mol Ther. 2021 May 5;29(5):1729-1743. doi: 10.1016/j.ymthe.2021.01.020. Epub 2021 Jan 21.

Abstract

Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.

Keywords: BASP1; EV engineering; IL-12; PTGFRN; exosome engineering; exosomes; extracellular vesicles; sacffold; vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication
  • Drug Delivery Systems
  • Extracellular Vesicles / genetics
  • Extracellular Vesicles / metabolism
  • Extracellular Vesicles / transplantation*
  • Female
  • HEK293 Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Proteins / administration & dosage*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*

Substances

  • BASP1 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • PTGFRN protein, human
  • Proteins
  • Repressor Proteins