Tailored Extracellular Vesicles: Novel Tool for Tissue Regeneration

Abstract

Extracellular vesicles (EVs) play an essential part in multiple pathophysiological processes including tissue injury and regeneration because of their inherent characteristics of small size, low immunogenicity and toxicity, and capability of carrying a variety of bioactive molecules and mediating intercellular communication. Nevertheless, accumulating studies have shown that the application of EVs faces many challenges such as insufficient therapeutic efficacy, a lack of targeting capability, low yield, and rapid clearance from the body. It is known that EVs can be engineered, modified, and designed to encapsulate therapeutic cargos like proteins, peptides, nucleic acids, and drugs to improve their therapeutic efficacy. Targeted peptides, antibodies, aptamers, magnetic nanoparticles, and proteins are introduced to modify various cell-derived EVs for increasing targeting ability. In addition, extracellular vesicle mimetics (EMs) and self-assembly EV-mimicking nanocomplex are applied to improve production and simplify EV purification process. The combination of EVs with biomaterials like hydrogel, and scaffolds dressing endows EVs with long-term therapeutic efficacy and synergistically enhanced regenerative outcome. Thus, we will summarize recent developments of EV modification strategies for more extraordinary regenerative effect in various tissue injury repair. Subsequently, opportunities and challenges of promoting the clinical application of engineered EVs will be discussed.

Extracellular vesicle-loaded hydrogels for tissue repair and regeneration

“…Hypoxia is only one of the more classic pretreatment strategies, but there are many others, such as the addition of lipopolysaccharides [ 66 ], hydrogen peroxide [ 66 ], hydrogen peroxide [ 67 ], atorvastatin [ 68 ], and pioglitazone [ 69 ]. EV activity can also be enhanced by engineering or genetic strategies, including surface modifications, genetic modification, and epigenetic reprogramming [ 41 , 70 , 71 ]. In addition, as excellent natural carriers, EVs have been loaded with nucleic acids, growth factors, natural drugs, and other molecules to enhance their biological activity [ 72 ].…”

Small extracellular vesicles: Yields, functionalization and applications in diabetic wound management

“…Hypoxia : Hypoxia has been observed to boost the secretion of sEVs, which may be mediated by hypoxia‐inducible factor‐1α (HIF‐1α) 44 . For human umbilical cord MSCs (hucMSCs), 5% O 2 hypoxic environment boosted the secretion of sEVs and the yield of sEVs was increased by about 90%, which might be attributed to the enhanced proliferation rate and viability of hucMSCs 45 .…”

“…In contrast, alterations in the culture environment have the potential to influence sEV functions by affecting the composition and types of cargoes present. For example, the application of hypoxia‐pretreatment not only leads to increased yields of MSC‐derived sEVs but also augments the content of angiogenic and anti‐inflammatory cargoes, encompassing miRNAs and proteins 44–48 . Culturing ARPE‐19 in culture medium containing ethanol 49 or 600 μM H 2 O 2 50 was observed to upregulate the expression of VEGFR on the membrane and more VEGFR mRNA in the lumen of sEVs, thus affecting the angiogenesis of obtained sEVs.…”

The Emerging Role of Extracellular Vesicles from Mesenchymal Stem Cells and Macrophages in Pulmonary Fibrosis: Insights into miRNA Delivery

“…Apoptotic bodies, another kind of EV, are 500–5000 nm in diameter. They are produced by dying cells and are even more abundant than exosomes or MVs under specific conditions [ 18 , 29 , 30 ]. Exosomes and microvesicles have been suggested as ‘safe containers’ mediating cell-to-cell communication, however, apoptotic bodies are derived from disassembling an apoptotic cell into subcellular fragments.…”

“…EV secretion appears to be an evolutionarily conserved procedure, and EV-based cell-to-cell communication occurs throughout all kingdoms of life [ 15 ]. EVs are often classified according to their diameter size, as exosomes (30 to 150 nm), microvesicles (50–1000 nm), or apoptotic bodies (500–5000 nm) [ 16 , 17 , 18 ]. In fact, size, which had been regarded as a decisive factor for distinguishing different vesicles, has been found to be less relevant due to size discrepancies observed by various measuring techniques [ 19 ].…”