The Multifunctionality of Exosomes; from the Garbage Bin of the Cell to a Next Generation Gene and Cellular Therapy

Abstract

Exosomes are packaged with a variety of cellular cargo including RNA, DNA, lipids and proteins. For several decades now there has been ongoing debate as to what extent exosomes are the garbage bin of the cell or if these entities function as a distributer of cellular cargo which acts in a meaningful mechanistic way on target cells. Are the contents of exosomes unwanted excess cellular produce or are they selective nucleic acid packaged nanoparticles used to communicate in a paracrine fashion? Overexpressed RNAs and fragments of DNA have been shown to collect into exosomes which are jettisoned from cells in response to particular stimuli to maintain homeostasis suggesting exosomes are functional trash bins of the cell. Other studies however have deciphered selective packaging of particular nucleic acids into exosomes. Nucleic acids packaged into exosomes are increasingly reported to exert transcriptional control on recipient cells, supporting the notion that exosomes may provide a role in signaling and intracellular communication. We survey the literature and conclude that exosomes are multifunctional entities, with a plethora of roles that can each be taken advantage to functionally modulate cells. We also note that the potential utility of developing exosomes as a next generation genetic therapy may in future transform cellular therapies. We also depict three models of methodologies which can be adopted by researchers intending to package nucleic acid in exosomes for developing gene and cell therapy.

Exposure to a Pathological Condition May Be Required for the Cells to Secrete Exosomes Containing mtDNA Aberration

“…However, all the primer sets successfully amplified the target genes when cytoplasmic DNAs were used as templates, indicating that mtDNAs associated with exosomes are fragmented. Fragmented mtDNAs are reported to be released from defective mitochondria during their turnover and hauled away for clearance by exosomes and other extracellular vesicles ( 38 ).…”

Extracellular vesicles: The next generation in gene therapy delivery

“…The resulting high concentration of cytoplasmic mRNA is sufficient to cause packaging of mRNA into EVs, perhaps because EVs have been found to functionally export cellular components that are in vast surplus. 11 Villamizar et al. transfected mesenchymal stem cells (MSCs) with a plasmid encoding for a zinc finger transcription factor targeted to the CFTR gene promoter for the treatment of cystic fibrosis (called CFZF).…”

“…However, this approach is onerous, produces heterologous populations of EVs, and may prove challenging to translate clinically. Moreover, the relative short ½ life of less than 48 h in vivo 11 indicates that multiple EV administrations would be required as a therapeutic strategy. An alternative approach would be to engineer cells, directly in vivo , to produce EVs with defined therapeutic payloads.…”

Nano‐delivery systems as a promising therapeutic potential for epilepsy: Current status and future perspectives

“…MVBs have two general destinies: they can attach to the lysosome and be degraded, or they can be fused to the cell membrane and release their intraluminal vesicles (ILVs), called exosomes, into the extracellular space 65 . It is interesting to note that exosomes were initially conceived as cellular wastes, but further research revealed that depending on their cellular origin, exosomes are packed with different functional molecules like messenger RNA (mRNA), DNA, long non‐coding RNA (LncRNA), and micro RNAs (miRNAs) that can be entered to recipient cells and impress their behavior and characteristics 67 . Therefore, exosomes act as natural nano‐carriers in the body and can be inspired to deliver various medications, including ASMs.…”