The Recent advances in gene delivery using nanostructures and future prospects

Advances in Applied NanoBio-Technologies 2020, Volume 1, Issue 2, Pages: 45-52
45
Recent advances in gene delivery using
nanostructures and future prospects
S.N.Abootalebi1,2*, E.Shorafa2
1
Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
2
Division of Pediatric Intensive Critical Care, Department of Pediatrics, School of Medicine, Shiraz University of Medical Sciences,
Shiraz, Iran.
Received: 08/05/2020 Accepted: 09/06/2020 Published: 20/06/2020
Abstract
Gene therapy has attracted much attention as an encouraging solution to treat a wide range of diseases rather than rare hereditary
and single-gene disorders. For this purpose, nucleic acids must be delivered to human target cells. This article reviews the history,
key issues, recent advances, and future of gene therapy using nanostructures. Some intracellular and extracellular barriers need to
be removed. Today, a wide range of nano-vectors vectors have been developed. Several vectors based on nanostructures have been
developed and used for the successful treatment of some inherited diseases, immunodeficiency, ocular and cancer. Viral vectors
are suitable for gene therapy for diseases that require long-term gene expression. Although non-viral vectors are less effective than
viruses, they are more specific, have less immunogenicity, and are capable of transmitting longer genes. Overall, recent advances
in various gene therapy strategies have been able to meet some of the expectations of gene therapy for years, and have raised many
hopes for further success. Gene therapy seems to be the ultimate solution of the present century to treat many human diseases.
Keywords: Gene therapy, Viral Vectors, Nanostructures, Cancer
1 Introduction
In the last two decades, extensive research in the field of gene
therapy has dramatically expanded. Generally, it can be defined
as "the transfer of genetic material using a vector into the cell
nucleus to alter gene expression, to prevent and treat a disease, or
to improve a patient's clinical condition." In this DNA treatment
model, the therapist can be inserted into the host chromosome or
remain as an episomal vector, depending on the vector used.
Ultimately, the goal of gene delivery is to modify the defective
genotype of the patient by replacing the defective allele of a gene
with its healthy and active type or eliminating the defective allele
(1). The transfer of genetic material in this method can be done
in-vitro or ex-vivo to autologous cells taken from the patient, and
then these cells are returned to the patient. Due to recent advances
in various gene therapy methods, gene therapy has been able to
provide promising results for the treatment of diseases caused by
a deficiency or defect of one or more genes. There are several
general strategies for achieving gene therapy goals that may be
Corresponding author: S.N. Abootalebi, Biotechnology
Research Center, Shiraz University of Medical Sciences, Shiraz,
Iran. & Division of Pediatric Intensive Critical Care, Department
of Pediatrics, School of Medicine, Shiraz University of Medical
Sciences, Shiraz, Iran.
Email: Abootalebinarjes@yahoo.com
used alone or in combination (2).
These solutions include:
1. Insert a normal gene into a non-specific region in the genome
and replace it with a non-functional gene. This solution is
currently the most commonly used method (3).
2. Replacement of an unhealthy gene with a healthy one through
homologous recombination (4)
3. Modification of unhealthy genes and restoration of its function
by inverse selective mutation (5).
4. Gene knockdown; a new tool for regulating a single gene or a
network of complex genes. In this technique, the gene is
environmentally regulated using miRNA, or RNAi is used to
approximate the deletion of gene products (6).
2 The first step in gene therapy: efficient and safe
gene delivery
The most critical challenge in gene therapy is finding the right
vector or carrier to get the gene into the cell nucleus. The main
barriers to effective gene delivery to the cell nucleus are
degradation of therapeutic polynucleotides in the extracellular
space, the inability of the carrier to enter the target cell, difficulty
in the intracellular transfer of polynucleotides from the endosome
to the lysozyme and its escape from the endosome, separation of
polynucleotides from vectors and lack of polynucleotides entering
the nucleus (7). Also, in vivo studies have other criteria such as
J. Adv. Appl. NanoBio Tech.
Journal web link: http://www.jett.dormaj.com
https://doi.org/10.47277/AANBT/1(2)52
https://doi.org/10.47277/AANBT/1(1)27

46
physicochemical properties (such as particle size and zeta
potential that are involved in the stability of the carrier in the
biological environment) (8) and the effect of the immune system
on the vector (such as the reticuloendothelial system) should also
be considered (9).
Figure 1. Four major obstacles to successful treatment of patients using
gene therapy (10):.
Accordingly, the technical problems facing successful gene
therapy can be divided into four groups:
2.1 Vector harvesting, transfer and separation of genes from
vectors
To perform successful gene therapy, it is first necessary that
the target tissue harvest the vector. Tissue diffusion of the vector
after administration is affected by several parameters such as
blood supply to the tissue and endothelial barriers of a particular
organ, the size of the vector and the interaction between the vector
ligands and the host cell receptors. Finally, it is desirable that the
vector used to reach a specific group of cells (11). Despite many
efforts, the design of a non-viral vector with specific ligands or
viral vectors with engineered capsids or coating proteins that
deliver the vector to the specific target cell is still technically
controversial. Finally, such designs have not been significantly
successful in clinical trials. These engineered vectors are too large
and very unstable and are not able to transfer from the cytoplasm
to the cell nucleus (12, 13). Viruses have an efficient mechanism
for transmission to cells and nuclei, but assuming that non-viral
vectors can cross cell membranes, there are still two serious
barriers to their transmission: their inability to escape the
endosome and their inability to cross membrane (14).
2.2 Vector genome persistence
If the exogenous DNA molecule in the vector remains
episomically in the nucleus, it will be destroyed after the first
period of cell division (15). However, if these episomal vectors
are transferred to tissues like liver, brain, heart, or muscle, they
can remain for many years, because these cells in these organs
have a prolonged life cycle (16). Vectors that integrate into the
host chromosome are a better choice for gene therapy in cells that
have a faster life cycle (such as hematopoietic cells) (17);
However, when using these vectors, there is a risk of activating or
destroying adjacent genes due to the potential for additional
mutagenesis (18).
2.3 Continuous gene expression
Sometimes the expression of the transferred gene may be
silenced due to epigenetic changes in the vector genome.
Generally, the duration of gene expression should be
commensurate with the period required to treat a particular
disease (19, 20). For example, most genetic diseases require gene
expression to continue for life, which can be achieved by repeated
administration of the vector or by stable expression of the gene
after a single injection; Infectious diseases or cancers, on the other
hand, require a more limited period of gene expression (21).
2.4 Host's immune response
The host immune system can react against the transgene
product or the vector itself; This is considered to be the most
fundamental barrier to gene delivery (22, 23). By aggregating
information and completing knowledge about a wide range of
host immune responses, creative solutions may be discovered to
slow the release of vector transfer and gene expression in a single
target cell group or cell types to increase cell response (24). They
are also less safe. The inability to predict the innate and antigen-
dependent immune response in humans is probably the biggest
obstacle to using new gene delivery technologies because some
human immune responses are not currently measurable in animal
models (25). Another reason for the failure of clinical trials is that
the relationship between animal and human studies is not
definitely accurate (26), and it cannot currently be claimed that
gene transfer to humans using a specific vector has the same
efficiency. Therefore, the most important challenge in gene
therapy is finding a suitable carrier to deliver the gene into the cell
nucleus (27). The early carriers used in gene therapy were very
simple. The history of different types of vectors, how they are
prepared and their therapeutic uses have been repeatedly studied
(28). The advances that have been made in the field of gene

47
transfer to cells or tissues over the past 15 years are largely due to
advances in vector technology. These technologies include a wide
range of advances in vector system purification, improving in
production methods, increasing transduction rates, and improving
vector-host safety profiles (29, 30).
Generally, gene delivery is done by two main methods: viral
carriers and non-viral methods (31). Viral carriers are older and
more efficient than non-viral methods because viruses are
naturally equipped with multiple mechanisms to cross cellular
barriers (13, 32). Despite the widespread use of these carriers,
especially in clinical trials, today non-viral methods have been
considered as a better alternative due to their higher safety, greater
diversity, ease of production, and industrializability (33).
3 Non-Viral Methods
Non-viral vectors have significant advantages over viral
vectors. Recent advances in the technology of these methods have
led to the relative elimination of its disadvantages (including low
rate of gene transfer and expression) and have led to the
development of vectors and techniques that are as effective as
viral vectors (34). The following is a summary of some of these
methods:
3.1 DNA injection
The simplest method of non-viral gene delivery is DNA
injection. This method is much less expensive than other gene
therapy methods, but the rate of gene expression in this method is
very low compared to other methods (35). There are several ways
to inject a gene. Some common ways to achieve this goal are:
3.1.1 Hydrodynamic gene delivery
Rapid injection of large volumes of solution containing naked
DNA into the tail vein in mice, which mainly causes gene delivery
to the liver. This method was the first attempt to deliver plasmid
DNA through systemic administration (35).
3.1.2 Injection of small volumes of naked DNA into the great
inferior vena cava
Mainly concentrates gene expression in epithelial cells near
the tubule in the kidney. This method resulted in 35-day stable
expression of beta-galactosidase gene without any significant
toxicity or side effects (36).
3.1.3 Intramuscular injection of naked plasmid DNA
This method has been successful in clinical trials (37).
3.2 Gene delivery by electric waves
It is a method that uses short pulses with high voltage to
transfer the gene into the cell (38). This electric shock appears to
create a temporary hole in the cell membrane, allowing the DNA
molecule to cross the membrane. This process is generally
considered an efficient method and can be used for a wide range
of cell types; However, due to the large number of cells killed
during this procedure, its use is severely limited, especially in
clinical trials.
3.3 Gene gun
One of the physical methods for DNA transfer is the use of
particle bombardment or gene gun. In this method, DNA is coated
with gold particles and then placed inside a device that exerts a
force on the gene and penetrates it into the cell (39). Despite its
undeniable efficiency, this method has one major drawback: if the
gene enters the wrong place in the host cell genome, such as the
tumor suppressor gene; It can lead to cancer. This occurred in a
clinical trial performed on X-SCID patients (40).
3.4 Gene delivery by sound waves
This technique uses ultrasonic frequencies to deliver DNA to
the cell. The pores created by sonic energy are thought to disrupt
cell membrane integrity and allow DNA to move into the cell
(41).
3.5 Magnetic field gene delivery
Today, a lot of research has been done on this process and the
term "magnetofection" is frequently used in scientific articles for
the "transfer of nucleic acids to the cell nucleus under a magnetic
field" (42). In this method, the carrier containing nucleic acids
forms a complex with magnetic nanoparticles and is added to the
supernatant of the culture medium. By placing a magnetic field in
cultured tissues, the DNA complexes are stimulated to enter the
cell nucleus (43, 44). This method is modeled on the concept of
targeted drug delivery using the magnetic field that was
considered in the 1970s (45). In this method, the DNA is
covalently or non-covalently bonded to nanomagnetic particles
and, accumulates or stored in the target position under suitable
magnetic gradient field (46, 47). The first study on gene delivery
by this method have been performed in 2002 by Mah et al.,
Showed that the binding AAV vector to magnetic microspheres
increases the efficiency of vector transduction (48). Although
there are several methods for binding vectors to magnetic
nanoparticles, the most common is binding through electrostatic
interactions. The mechanism by which the vector enters the cell
during the magnetofection process is probably no different from
standard transduction (49).
3.6 PEGylated multi-component nanostructures
These carriers are currently one of the most promising non-
viral methods for systemic gene delivery (50, 51). The
components of these carriers are:
3.6.1 Cationic carrier molecules
cationic polymers that compress polynucleotides and protect
against nuclease damage, such as protamine and PEI (52).

48
3.6.2 Hydrophilic polymers
Mainly contains different types of negatively-charged PEGs
that cover the positively-charged of the cationic carrier and
prevent the carrier from accumulating in the blood and being
picked up by RES (53). Detaching the carrier increases
persistence in the blood, spatial stability and accumulation of
carrier in vascular-rich tissues.
3.6.3. Targeting ligands
These molecules increase carrier uptake through the receptor-
dependent endocytosis tissue-specifically. Examples of these
ligands are: antibodies, PEI, RGD, EGF, DOPE (54).
3.6.4. Endosome scaping
These substances rupture the endosome and release
encapsulated polynucleotides due to the absorption of acidic
compounds (55). Examples of these materials are: DOPE and PEI.
3.6.5. Nuclear aggregation markers
These peptides direct polynucleotides into the nucleus (56).
Example: Tat and Rev
3.7 Oligonucleotides
Synthetic oligonucleotides are used to inactivate genes
involved in the development of a disease (57). The use of specific
antisense to stop transcription of the defective gene, or the use of
SiRNA molecule to destroy specific sequences of mRNA
transcription of the defective gene and thus stop the expression of
that gene, is some of the solutions used in this field. The problem
of this method is the difficulty of systemically administering
oligonucleotides, which have so far been explored in various
ways, such as cholesterol binding, conjugation with protamine
and target ligand, or complexation with polymers such as PEG
(58, 59). In addition, SiRNA strongly stimulates the immune
system and intracellular uptake. Adding a 2'-O-methyl uridine or
2'-O-methyl guanosine nucleoside to the end of a string of two
SiRNA strands solves this problem well (60).
3.8 Lipoplexes and polyplexes
These nanopolymers were modeled on natural or neutrally
charged lipids and later synthetic and more complex types were
designed and manufactured. These nanopolymers are used to coat
the positive charged-DNA and protect it in the biological
environment and during cell entry (61). The major problem of
lipoplexes is the rapid activation of the innate immune system and
the proliferation of proinflammatory cytokines (62). Reducing the
interaction between lipoplex and immune system, using
immunosuppressive agents, and removing the CpG portion of the
end of the plasmid DNA are three general solutions to this
problem (63).
3.9 Dendrimers
Macromolecules with a large number of lateral branches that
take on a total spherical shape (64). Covering the surface of these
macromolecules with various functional groups gives them
various properties. In fact, the unique characteristics of a
dendrimer are defined by the specific characteristics of its surface.
Cationic dendrimers, which have abundant positive electric
charges on their surface, temporarily bind to nucleic acids and
form complexes (65). This complex is picked up by the cell
through endocytosis (66).
3.10 Bactofection
In this method, bacteria are used as carriers of nucleic acids for
gene delivery (67). Different classes of invasive bacteria can enter
eukaryotic cells naturally by expressing different proteins. This
property of bacteria is used to transmit genes. So far, bactofection
has been performed in vivo and in vitro using several bacteria
including Shigella flexneri, Salmonella typhi, Listeria
monocytogenes, Pseudomonas aeruginosa, Staphylococcus
aureus and the recombinant invasive strain of Escherichia coli
(67, 68). Simplicity of application and relatively selective gene
transfer is the main advantage of bactofection, but its main
problem is the possibility of unwanted side effects caused by the
relationship between the bacterium and the host cell (69).
3.11 Hybrid methods
Since gene delivery methods each have advantages and
disadvantages, to increase their efficiency, several hybrid
methods have been developed that are a combination of two or
more techniques. Virosomes are one of these methods, which is
obtained by combining liposomes with the inactivated type of
HIV or influenza virus. This hybrid method was able to deliver
genes to the epithelial cells of the respiratory tract much more
efficiently than both viral and liposomal methods (70).
In addition to the vectors presented in this section, other vectors
have been used experimentally that are not very significant in
terms of clinical significance. Briefly, the vectors used in clinical
trials up to 2019 are listed in Table 1. As it turns out, the most
popular vectors for clinical use are still among the viral vectors.
Table 1. Vectors used in clinical trials until 2019.
Vectors Clinical Trials for gene therapy
Numbers Percent
Adenovirus 463 22.3
Retrovirus 406 19.6
Naked/Plasmid
DNA
369 17.8

49
Vaccinia virus 119 5.7
Adeno-associated
virus
117 5.6
Lipofection 113 5.4
Lentivirus 89 4.3
Unknown 71 3.4
Poxvirus 68 3.3
Herpes simplex
virus
63 3
RNA transfer 35 1.7
Poxvirus +
Vaccinia virus
32 1.5
Adenovirus +
Modified vaccinia
Ankara virus
(MVA)
10 0.5
Adenovirus +
Vaccinia virus
8 0.4
Flavivirus 8 0.4
Listeria
monocytogenes
9 0.4
Saccharomyces
cerevisiae
8 0.4
Sleeping Beauty
transposon
8 0.4
Antisense
oligonucleotide
6 0.3
Lactococcus lactis 6 0.3
Measles virus 7 0.3
Modified Vaccinia
Ankara virus
(MVA)
7 0.3
Gene gun 5 0.2
RNA virus 5 0.2
Salmonella
typhimurium
4 0.2
Adenovirus +
Retrovirus
3 0.1
E. coli 2 0.1
mRNA
Electroporation
2 0.1
Naked/Plasmid
DNA +
Adenovirus
3 0.1
Naked/Plasmid
DNA + Modified
Vaccinia Ankara
virus (MVA)
2 0.1
Naked/Plasmid
DNA + Vaccinia
virus
3 0.1
Naked/Plasmid
DNA + Vesicular
stomatitis virus
2 0.1
Semliki forest
virus
2 0.1
Sendai virus 2 0.1
siRNA 2 0.1
Venezuelan
equine
encephalitis virus
replicon
3 0.1
Vesicular
stomatitis virus
3 0.1
Adenovirus +
Sendai virus
1 0

50
Alphavirus (VEE)
Replicon Vaccine
1 0
Bifidobacterium
longum
1 0
Minimalistic,
immunologically
defined gene
expression
(MIDGE)
1 0
Newcastle disease
virus
1 0
Poliovirus 1 0
Shigella
dysenteriae
1 0
Simian
Immunodeficiency
Virus (SIVagm)
1 0
Simian virus 40 1 0
Streptococcus
mutans
1 0
Vibrio cholera 1 0
Total 2076
4 Conclusions and perspectives
Successful implementation of gene therapy has been a time-
consuming and erosive process. New medical treatments have
slow development due to the time required to perform safety tests.
Many initial clinical trials were abandoned incompletely because
there was insufficient scientific and clinical evidence for their
success. Now, more than 25 years after the start of gene therapy,
there is evidence of the expected clinical success, and preclinical
achievements promise a more successful future. Research to
optimize physical gene delivery methods is still ongoing; Immune
responses induced by plasmid DNA, siRNA and non-viral vectors
are managed; Several nanocarriers are designed to improve
systemic gene delivery; Knowledge of the mechanism of
intracellular transfer of plasmid DNA is accumulating; Several
tissue-specific plasmid vectors have been designed and studied to
induce long-term gene expression; The new peptide ligands are
designed to target gene delivery through phage display
technology and will soon be used in gene delivery; Since 2004,
researchers have used new technologies to efficiently and safely
deliver non-viral genes through systemic administration; But
despite significant advances, there is still a long way to go to find
a full-fledged carrier that can be used in bed. Many mechanistic
studies are still needed to better understand barriers to in-vivo
gene delivery. Urgent efforts to find the right carrier as well as a
better understanding of the interactions between the carrier and
the human host are obvious needs for gene therapy. It is essential
to design methods other than PEGylation to protect carriers
against hepatic RES. However, in the future, advanced
technologies such as RNA aptamer and RNA display will play a
key role in the development of high-performance target ligands.
Another area of gene therapy that needs to be studied more closely
is overcoming the toxic effects of gene transfer nanocarriers
against cells and tissues. Most of the basic studies of gene therapy
in the coming years will probably focus on the two axes of
developing gene delivery methods and overcoming the host
immune response.
Ethical issue
Authors are aware of, and comply with, best practice in
publication ethics specifically with regard to authorship
(avoidance of guest authorship), dual submission, manipulation
of figures, competing interests and compliance with policies on
research ethics. Authors adhere to publication requirements that
submitted work is original and has not been published elsewhere
in any language.
Competing interests
The authors declare that there is no conflict of interest that
would prejudice the impartiality of this scientific work.
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