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FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver.

Marcus ME, Leonard JN - Pharmaceuticals (Basel) (2013)

Bottom Line: Importantly, exosome-mediated delivery of such cargo molecules results in functional modulation of the recipient cell, and such modulation is sufficiently potent to modulate disease processes in vivo.A complementary perspective is that understanding the mechanisms of exosome-mediated transport may provide opportunities for "reverse engineering" such mechanisms to improve the performance of synthetic delivery vehicles.In this review, we summarize recent progress in harnessing exosomes for therapeutic RNA delivery, discuss the potential for engineering exosomes to overcome delivery challenges and establish robust technology platforms, and describe both potential challenges and advantages of utilizing exosomes as RNA delivery vehicles.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Biological Sciences Graduate Program, Northwestern University Evanston, IL 60208-3120, USA.

ABSTRACT
Many aspects of intercellular communication are mediated through "sending" and "receiving" packets of information via the secretion and subsequent receptor-mediated detection of biomolecular species including cytokines, chemokines, and even metabolites. Recent evidence has now established a new modality of intercellular communication through which biomolecular species are exchanged between cells via extracellular lipid vesicles. A particularly important class of extracellular vesicles is exosomes, which is a term generally applied to biological nanovesicles ~30-200 nm in diameter. Exosomes form through invagination of endosomes to encapsulate cytoplasmic contents, and upon fusion of these multivesicular endosomes to the cell surface, exosomes are released to the extracellular space and transport mRNA, microRNA (miRNA) and proteins between cells. Importantly, exosome-mediated delivery of such cargo molecules results in functional modulation of the recipient cell, and such modulation is sufficiently potent to modulate disease processes in vivo. It is possible that such functional delivery of biomolecules indicates that exosomes utilize native mechanisms (e.g., for internalization and trafficking) that may be harnessed by using exosomes to deliver exogenous RNA for therapeutic applications. A complementary perspective is that understanding the mechanisms of exosome-mediated transport may provide opportunities for "reverse engineering" such mechanisms to improve the performance of synthetic delivery vehicles. In this review, we summarize recent progress in harnessing exosomes for therapeutic RNA delivery, discuss the potential for engineering exosomes to overcome delivery challenges and establish robust technology platforms, and describe both potential challenges and advantages of utilizing exosomes as RNA delivery vehicles.

No MeSH data available.


Related in: MedlinePlus

Conceptual overview of exosome-based therapeutics: (1) Exosome biogenesis. Exosomes incorporate membrane components from the plasma and endosomal membranes, cytoplasmic proteins and RNA. Plasma membrane proteins reach exosomes via endocytosis into the endosomes followed by invagination of the endosomal membrane to form intraluminal vesicles (intracellular precursors of exosomes). An endosome containing many such intraluminal vesicles is termed a multivesicular body. Upon invagination of the endosomal membrane, endosomal membrane proteins also get incorporated into intraluminal vesicles. During invagination, cytoplasmic contents including RNA and proteins are engulfed into the lumen of the intraluminal vesicles. Upon backfusion of the multivesicular body with the plasma membrane, intraluminal vesicles are released into the extracellular space and are then termed exosomes. (2) Ex vivo modification of exosomes. Nucleic acids can be introduced to the exosome lumen via electroporation, and lipophilic small molecules can be passively loaded. (3) Exosome delivery. Exosomes are internalized by recipient cells via macropinocytosis, receptor-mediated endocytosis, or lipid raft-mediated endocytosis, each of which results in exosomes being taken up into endosomes. Exosomal contents are then released into the cytoplasm via backfusion with the endosomal membrane. Alternatively, exosomes can fuse directly with the recipient cell plasma membrane to release exosomal contents into the cytoplasm. Mechanisms of internalization utilized depend on the ligands displayed on the exosome surface, the cell type from which the exosomes are derived, and the recipient cell type.
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pharmaceuticals-06-00659-f001: Conceptual overview of exosome-based therapeutics: (1) Exosome biogenesis. Exosomes incorporate membrane components from the plasma and endosomal membranes, cytoplasmic proteins and RNA. Plasma membrane proteins reach exosomes via endocytosis into the endosomes followed by invagination of the endosomal membrane to form intraluminal vesicles (intracellular precursors of exosomes). An endosome containing many such intraluminal vesicles is termed a multivesicular body. Upon invagination of the endosomal membrane, endosomal membrane proteins also get incorporated into intraluminal vesicles. During invagination, cytoplasmic contents including RNA and proteins are engulfed into the lumen of the intraluminal vesicles. Upon backfusion of the multivesicular body with the plasma membrane, intraluminal vesicles are released into the extracellular space and are then termed exosomes. (2) Ex vivo modification of exosomes. Nucleic acids can be introduced to the exosome lumen via electroporation, and lipophilic small molecules can be passively loaded. (3) Exosome delivery. Exosomes are internalized by recipient cells via macropinocytosis, receptor-mediated endocytosis, or lipid raft-mediated endocytosis, each of which results in exosomes being taken up into endosomes. Exosomal contents are then released into the cytoplasm via backfusion with the endosomal membrane. Alternatively, exosomes can fuse directly with the recipient cell plasma membrane to release exosomal contents into the cytoplasm. Mechanisms of internalization utilized depend on the ligands displayed on the exosome surface, the cell type from which the exosomes are derived, and the recipient cell type.

Mentions: Exosomes have been discovered in the supernatants of a wide variety of cells in culture, and are present in all human bodily fluids, suggesting that they can be produced by any type of cell [8]. Exosomes are the extracellular equivalent of intraluminal vesicles (ILVs). ILVs are formed when the limiting membrane of an endosome buds inward, forming an internal vesicle (Figure 1). Endosomes containing ILVs are known as multivesicular endosomes or multivesicular bodies (MVBs). Although some MVBs traffic along the endosomal pathway towards the lysosome, other MVBs back fuse with the plasma membrane, releasing their contents, including ILVs, into the extracellular space. ILVs that have been released into the extracellular space are known as exosomes. Exosomes are therefore topologically equivalent to cells, encapsulating cellular cytoplasmic contents in the exosomal lumen and presenting membrane protein domains on the exosomal exterior that correspond to domains presented at the cell surface and in the lumen of the endoplasmic reticulum [9].


FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver.

Marcus ME, Leonard JN - Pharmaceuticals (Basel) (2013)

Conceptual overview of exosome-based therapeutics: (1) Exosome biogenesis. Exosomes incorporate membrane components from the plasma and endosomal membranes, cytoplasmic proteins and RNA. Plasma membrane proteins reach exosomes via endocytosis into the endosomes followed by invagination of the endosomal membrane to form intraluminal vesicles (intracellular precursors of exosomes). An endosome containing many such intraluminal vesicles is termed a multivesicular body. Upon invagination of the endosomal membrane, endosomal membrane proteins also get incorporated into intraluminal vesicles. During invagination, cytoplasmic contents including RNA and proteins are engulfed into the lumen of the intraluminal vesicles. Upon backfusion of the multivesicular body with the plasma membrane, intraluminal vesicles are released into the extracellular space and are then termed exosomes. (2) Ex vivo modification of exosomes. Nucleic acids can be introduced to the exosome lumen via electroporation, and lipophilic small molecules can be passively loaded. (3) Exosome delivery. Exosomes are internalized by recipient cells via macropinocytosis, receptor-mediated endocytosis, or lipid raft-mediated endocytosis, each of which results in exosomes being taken up into endosomes. Exosomal contents are then released into the cytoplasm via backfusion with the endosomal membrane. Alternatively, exosomes can fuse directly with the recipient cell plasma membrane to release exosomal contents into the cytoplasm. Mechanisms of internalization utilized depend on the ligands displayed on the exosome surface, the cell type from which the exosomes are derived, and the recipient cell type.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3722064&req=5

pharmaceuticals-06-00659-f001: Conceptual overview of exosome-based therapeutics: (1) Exosome biogenesis. Exosomes incorporate membrane components from the plasma and endosomal membranes, cytoplasmic proteins and RNA. Plasma membrane proteins reach exosomes via endocytosis into the endosomes followed by invagination of the endosomal membrane to form intraluminal vesicles (intracellular precursors of exosomes). An endosome containing many such intraluminal vesicles is termed a multivesicular body. Upon invagination of the endosomal membrane, endosomal membrane proteins also get incorporated into intraluminal vesicles. During invagination, cytoplasmic contents including RNA and proteins are engulfed into the lumen of the intraluminal vesicles. Upon backfusion of the multivesicular body with the plasma membrane, intraluminal vesicles are released into the extracellular space and are then termed exosomes. (2) Ex vivo modification of exosomes. Nucleic acids can be introduced to the exosome lumen via electroporation, and lipophilic small molecules can be passively loaded. (3) Exosome delivery. Exosomes are internalized by recipient cells via macropinocytosis, receptor-mediated endocytosis, or lipid raft-mediated endocytosis, each of which results in exosomes being taken up into endosomes. Exosomal contents are then released into the cytoplasm via backfusion with the endosomal membrane. Alternatively, exosomes can fuse directly with the recipient cell plasma membrane to release exosomal contents into the cytoplasm. Mechanisms of internalization utilized depend on the ligands displayed on the exosome surface, the cell type from which the exosomes are derived, and the recipient cell type.
Mentions: Exosomes have been discovered in the supernatants of a wide variety of cells in culture, and are present in all human bodily fluids, suggesting that they can be produced by any type of cell [8]. Exosomes are the extracellular equivalent of intraluminal vesicles (ILVs). ILVs are formed when the limiting membrane of an endosome buds inward, forming an internal vesicle (Figure 1). Endosomes containing ILVs are known as multivesicular endosomes or multivesicular bodies (MVBs). Although some MVBs traffic along the endosomal pathway towards the lysosome, other MVBs back fuse with the plasma membrane, releasing their contents, including ILVs, into the extracellular space. ILVs that have been released into the extracellular space are known as exosomes. Exosomes are therefore topologically equivalent to cells, encapsulating cellular cytoplasmic contents in the exosomal lumen and presenting membrane protein domains on the exosomal exterior that correspond to domains presented at the cell surface and in the lumen of the endoplasmic reticulum [9].

Bottom Line: Importantly, exosome-mediated delivery of such cargo molecules results in functional modulation of the recipient cell, and such modulation is sufficiently potent to modulate disease processes in vivo.A complementary perspective is that understanding the mechanisms of exosome-mediated transport may provide opportunities for "reverse engineering" such mechanisms to improve the performance of synthetic delivery vehicles.In this review, we summarize recent progress in harnessing exosomes for therapeutic RNA delivery, discuss the potential for engineering exosomes to overcome delivery challenges and establish robust technology platforms, and describe both potential challenges and advantages of utilizing exosomes as RNA delivery vehicles.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Biological Sciences Graduate Program, Northwestern University Evanston, IL 60208-3120, USA.

ABSTRACT
Many aspects of intercellular communication are mediated through "sending" and "receiving" packets of information via the secretion and subsequent receptor-mediated detection of biomolecular species including cytokines, chemokines, and even metabolites. Recent evidence has now established a new modality of intercellular communication through which biomolecular species are exchanged between cells via extracellular lipid vesicles. A particularly important class of extracellular vesicles is exosomes, which is a term generally applied to biological nanovesicles ~30-200 nm in diameter. Exosomes form through invagination of endosomes to encapsulate cytoplasmic contents, and upon fusion of these multivesicular endosomes to the cell surface, exosomes are released to the extracellular space and transport mRNA, microRNA (miRNA) and proteins between cells. Importantly, exosome-mediated delivery of such cargo molecules results in functional modulation of the recipient cell, and such modulation is sufficiently potent to modulate disease processes in vivo. It is possible that such functional delivery of biomolecules indicates that exosomes utilize native mechanisms (e.g., for internalization and trafficking) that may be harnessed by using exosomes to deliver exogenous RNA for therapeutic applications. A complementary perspective is that understanding the mechanisms of exosome-mediated transport may provide opportunities for "reverse engineering" such mechanisms to improve the performance of synthetic delivery vehicles. In this review, we summarize recent progress in harnessing exosomes for therapeutic RNA delivery, discuss the potential for engineering exosomes to overcome delivery challenges and establish robust technology platforms, and describe both potential challenges and advantages of utilizing exosomes as RNA delivery vehicles.

No MeSH data available.


Related in: MedlinePlus