A functional corona around extracellular vesicles enhances angiogenesis, skin regeneration and immunomodulation

J Extracell Vesicles. 2022 Apr;11(4):e12207. doi: 10.1002/jev2.12207.

Abstract

Nanoparticles can acquire a plasma protein corona defining their biological identity. Corona functions were previously considered for cell-derived extracellular vesicles (EVs). Here we demonstrate that nano-sized EVs from therapy-grade human placental-expanded (PLX) stromal cells are surrounded by an imageable and functional protein corona when enriched with permissive technology. Scalable EV separation from cell-secreted soluble factors via tangential flow-filtration (TFF) and subtractive tandem mass-tag (TMT) proteomics revealed significant enrichment of predominantly immunomodulatory and proangiogenic proteins. Western blot, calcein-based flow cytometry, super-resolution and electron microscopy verified EV identity. PLX-EVs partly protected corona proteins from protease digestion. EVs significantly ameliorated human skin regeneration and angiogenesis in vivo, induced differential signalling in immune cells, and dose-dependently inhibited T cell proliferation in vitro. Corona removal by size-exclusion or ultracentrifugation abrogated angiogenesis. Re-establishing an artificial corona by cloaking EVs with fluorescent albumin as a model protein or defined proangiogenic factors was depicted by super-resolution microscopy, electron microscopy and zeta-potential shift, and served as a proof-of-concept. Understanding EV corona formation will improve rational EV-inspired nano-therapy design.

Keywords: EV corona; EV function; angiogenesis; extracelular vesicle; placenta derived stromal cells; tangential flow filtration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Extracellular Vesicles* / metabolism
  • Female
  • Humans
  • Immunomodulation
  • Placenta
  • Pregnancy
  • Protein Corona* / metabolism
  • Proteomics

Substances

  • Protein Corona