Exosomes are natural nanoparticles that are widely distributed in tissues and can be produced by all known cells. More and more studies have shown that exosomes can regulate a variety of biological functions.

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Drug Delivery Systems: Exosomes VS
Liposomes
Exosomes are natural nanoparticles that are widely distributed in tissues and can be
produced by all known cells. More and more studies have shown that exosomes can
regulate a variety of biological functions.
1. Nature's Intercellular Messenger
In nature, exosomes protect and deliver functional macromolecules, including nucleic
acids, proteins, lipids, and carbohydrates. Exosomes alter the behavior of recipient cells
by transferring macromolecules to recipient cells or activating signaling pathways. Such
as transcription and translation, tissue repair, immune balance, cell differentiation and
regeneration, apoptosis, cell migration, metabolic regulation, and microbial environment,
these are far from covering the extensive research work in academia in recent years.
Based on these unique advantages of exosomes, it is expected to be a cell-free
therapy for multiple indications.
Figure 1 Intercellular communication via exosomes

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2. Therapeutic Potential
The expectation for exosomes as drug carriers is rooted in the unique structure of
exosomes. Its structure is simple, the outside is a membrane composed of a phospholipid
bilayer, and the membrane is rich in protein distribution, and the inside is a cavity, which
can be loaded with macromolecules, small molecules and nucleic acids. The cavity is a
space we can use for drug delivery. The existence of external proteins is very valuable.
On the one hand, it can provide low immunogenicity and great potential for repeatable
administration. On the other hand, these proteins can be used for surface modification,
loading macromolecules, and improving targeting.
Figure 2 Exosome structure
The medical potential of exosomes mainly includes three major directions (Figure 3):

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A. Potential of exosomes in diagnostic prevention: Exosomes extracted from the case
microenvironment can be used as biomarkers for the diagnosis of specific diseases and
injuries.
B. Medical potential of exosomes: Exosomes are produced by a variety of cells and
interact with target cells in various ways to produce medical effects.
C. Drug delivery potential of exosomes: Exosomes can be used to deliver a variety of
drugs such as RNA, proteins, and small molecules.
Figure 3 Potential applications of exosomes
3. Application of Drug Delivery System (DDS)

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One factor to consider in Drug Delivery System (DDS) development is drug
encapsulation efficiency, since exosomes are biological products derived from cellular
activity, they have less freedom to adapt to their lipid membranes and internal composition
compared to liposomal delivery systems.
A. There are two main strategies for loading drugs into exosomes: 1) Loading drugs by
adding and manipulating exosome donor cells prior to exosome separation. The strategy
requires the compatibility and suitability of parent cells with drugs to be encapsulated in
exosomes. 2) Drug loading after exosome separation. This strategy requires preserving
the structure and function of vesicles.
To comprehensively evaluate any therapeutic delivery vehicle, detailed testing of
pharmacodynamics and pharmacokinetics in preclinical models similar to the human
condition is critical.
B.To date, published preclinical studies of exosomes as DDS are only in mice, rats and
zebrafish. Pigs have been used as preclinical tests for exosome therapy itself, but not as
DDS, and there is no published record of studies in non-human primates.
C. Disease indications cover neurodegenerative diseases, cardiovascular diseases,
tumors, inflammation, etc.

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Figure 4 Schematic representation of exosomes as DDS in preclinical animal models
4.Comparison of Liposome And Exosome Administration
The main challenges in delivering therapeutic agents to the site of action are off-target
toxicity, rapid clearance, and low accumulation and bioavailability in target tissues, cells,
or organelles. To circumvent these challenges, a wide range of synthetic delivery vectors
(liposomes, lipid nanoparticles, polymer micelles, inorganic nanoparticles, dendrimers,
etc.) have been developed over the past few decades, some of which have been clinically
approved. Of all the available maps of nanoparticles, the most successful and clinically
approved vector on the market to date is liposome. Due to the similarity between
liposomes and exosomes, physicochemical properties and drug delivery capabilities of
the two will be compared next.
A. Liposomes: Lipid drugs are loaded into the bilayer membrane; ligands can be
incorporated to increase tissue targeting specificity; hydrophilic drugs can be loaded in the
lumen of liposomes. Onpattro is the first siRNA-loaded lipid nanoparticle approved by the
U.S. Food and Drug Administration (FDA) and consists of ionizable lipids, cholesterol,
PEGylated lipids, and helper lipids.

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B. Exosomes: Proteins, hydrophilic drugs, and nucleic acids (miRNA, siRNA, mRNA, etc.)
can be loaded into the lumen of vesicles, while targeting ligands, membrane proteins, and
lipophilic drugs can be incorporated into the membrane.
Figure 5 Liposomes and exosomes
Physical Characteristics, Production and Quality Control
Liposomes are structurally similar to exosomes in that they are composed of lipid bilayers.
Similarly, exosomes can carry hydrophobic drugs within the lipid membrane bilayer and
hydrophilic drugs in the aqueous core. Furthermore, clinically approved liposomes are
approximately 100 nm in size, similar to exosomes. In addition, the size of liposomes
allows for intravenous administration and extravasation in certain parts of the body after
cell uptake.
Despite their similarities, there are many differences between liposomes
and Extracellular Vesicles (EVs) as drug delivery vehicles. Compared to exosomes,
liposomes for clinical use are composed of a limited number of lipids but have no cellular

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components such as proteins and genetic material, so they are relatively easy to handle
during pharmaceutical quality control and large-scale production.
However, exosomes are rich in sphingomyelin, cholesterol, and lysophospholipids, so
exosomes can achieve a higher degree of complexity than mixing individual components
in liposomes. In addition, due to the presence of biomolecules in the membrane and core,
additional binding pockets may exist in exosomes for drug loading. This requires higher
requirements for manufacturing and quality control, and scaling up of exosomes has so far
been extremely challenging in terms of production and harvesting.
In Vivo Administration of Exosomes And Liposomes
Nanoparticles (exosomes and liposomes) are rapidly cleared by the mononuclear
phagocyte system (MPS). Liposomes represent biodegradable and biocompatible DDS
with very versatile high-throughput preparation and drug encapsulation efficiency,
allowing lyophilization and surface modification. To reduce immunogenicity and avoid
rapid blood clearance of liposomes, polyethylene glycol (PEG) surface coatings are widely
used, allowing more accumulation in target tissues. Decorating exosomes with PEG or
PEG-conjugated targeting ligands has been proposed as a promising strategy to enhance
the drug delivery capacity of exosomes. Another interesting strategy is to select a subset
of exosomes containing specific surface proteins such as CD47. This protein acts as a
"don't eat me" signal in exosomes and may give them the ability to bypass MPS and
exhibit longer circulation times.
Biodistribution
All approved liposomal drugs on the market rely on passive targeting, and only a small
percentage of active targeting agents have reached the clinical stage. This is because
even when surface ligands are used to target specific receptors on target cells, the
accumulation of liposomes is still thought to be determined by a passive extravasation
process known as the enhanced permeability and retention (EPR) effect. Through the

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EPR effect, liposomes with longer circulation times tend to accumulate in tumors or
damaged myocardium.
Pharmacokinetics and Pharmacodynamics (PK/PD)
PK/PD, as a simulation system based on the physiological and pharmacological effects of
drugs, can provide valuable information for the therapeutic efficacy of
drugs. Encapsulation of the drug in the liposome prevents rapid clearance and
significantly alters the PK characteristics of the drug compared to the free form. Exosomes
may have the potential to reduce MPS-mediated clearance compared to liposomes due to
the presence of surface CD47, but more evidence is needed. Due to the challenges of
large-scale exosome production and the presence of endogenous exosomes, little
information is available on the PK/PD characteristics of exosomes. A comprehensive
understanding of the PK/PD properties of exosomes as DDS is critical for exosomes to
reach the clinic.
Conclusion
Exosomes, which have received a lot of attention in the field of biomedicine in recent
years, have unique advantages, such as easy loading of multiple molecules, potential for
targeting, potential for engineering, low immunogenicity, and suitable for repeated
administration. As a new research hotspot, exosomes have become a potentially effective
method for disease diagnosis and treatment, and have bright prospects. Of course,
exosomes have some limitations of their own. At the present stage, the research on
exosomes is not abundant, so the productivity is relatively low, which is also a direction
that needs to be improved in this field. Although, the use of exosomes as drug or gene
delivery vehicles is still in its infancy. We believe that with the deepening of exosome
research, exosome therapy may eventually lead to major breakthroughs in the field of
drug or gene delivery.

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Polyethylene glycol (PEG) is widely utilized in drug delivery and nanotechnology due to its
reported“stealth”properties and biocompatibility. Biopharma PEG has been focusing on
the development of a full range of medical applications and technologies for nanocarrier
systems (including various types of nanoparticles, liposomes, micelles, etc.), and has
accumulated a large number of data models and rich research experience in the
construction and optimization of nanocarriers for gene vaccines and protein drugs.
References:
1. Lee, Vincent H L, and Hamidreza Ghandehari. “Advanced drug delivery: perspectives
and prospects. Preface.”Advanced drug delivery reviews vol. 65,1 (2013): 1-2.
doi:10.1016/j.addr.2012.12.001
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