- Open Access
Regulation of cellular gene expression by nanomaterials
© The Author(s) 2018
- Received: 1 November 2018
- Accepted: 15 November 2018
- Published: 30 November 2018
Within a cell there are several mechanisms to regulate gene expression during cellular metabolism, growth, and differentiation. If these do not work properly, the cells will die or develop abnormally and, in some cases, even develop into tumors. Thus, a variety of exogenous and endogenous approaches have been developed that act on essential stages of transcription and translation by affecting the regulation of gene expression in an intended manner. To date, some anticancer strategies have focused on targeting abnormally overexpressed genes termed oncogenes, which have lost the ability to tune gene expression. With the rapid advent of nanotechnology, a few synthetic nanomaterials are being used as gene regulation systems. In many cases, these materials have been employed as nanocarriers to deliver key molecules such as silencing RNAs or antisense oligonucleotides into target cells, but some nanomaterials may be able to effectively modulate gene expression due to their characteristic properties, which include tunable physicochemical properties due to their malleable size and shape. This technology has improved the performance of existing approaches for regulating gene expression and led to the development of new types of advanced regulatory systems. In this short review, we will present some nanomaterials currently used in novel gene regulation systems, focusing on their basic features and practical applications. Based on these findings, it is further envisioned that next-generation gene expression regulation systems involving such nanomaterials will be developed.
- Gene regulation
- Cellular transport
- RNA interference
The first discovery regarding the regulation of gene expression in natural systems was reported in 1961 by Francois Jacob and Jacques Monod, who studied the Lac operon within E. coli . The operon is a unit composed of a structural gene, promoter, and operator. In particular, the Lac operon is a simple unit that regulates the expression of an enzyme involved in lactose metabolism in E. coli. Gene regulation inside the cell usually maintains the level of the respective product at a proper concentration and primarily plays an important role in overall cellular metabolism, such as preventing extraneous gene expression or controlling cell growth, proliferation, and differentiation [2–4].
Proper expression of gene products involves regulation of each stage in the central dogma of molecular biology . During the transcription process, regulation is mainly achieved by suppressing the selective and obligatory affinity of RNA polymerases for template DNA. Regulation can also occur through increasing the number of DNA supercoils and thus decreasing the amount of exposed template DNA . In addition to physical regulation by induced supercoiling of DNAs, DNA methylation has been widely proposed to have a permanent regulatory effect through modification of the natural DNA structure, thus blocking the selective binding of some transcriptional factors . The Lac operon is acknowledged to be a representative system for the genetic regulation of template DNAs engaged with RNA polymerases during the course of gene transcription. Most regulatory procedures in the translation process take place at the initiation stage where mRNAs produced through the earlier transcription process are grabbed and read thoroughly by a functional ribosome that is essentially a protein-producing factory. As with the transcription process, translational gene regulation occurs by thwarting the accidental encounter of mRNAs and ribosomes . RNA interference, which is simply abbreviated as RNAi, has been revealed as a natural defense mechanism in plants that suppresses the expression of genes from some foreign bacteria or viruses at the level of translation .
Gene regulation has a variety of purposes. For example, genes expressed in the Lac operon are incorporated into template DNAs in a competitive manner with the corresponding RNA polymerase such that the concentration of lactose species is properly maintained in the cell. The MYC family of regulatory genes encodes transcription factors involved in cell growth, proliferation, and differentiation. Especially, for a gene that regulates cell growth such as MYC, dysregulated expression can trigger some life-threatening diseases such as cancer . MYC is one of the best-known oncogenes and is currently being considered as a target gene for both the treatment and diagnosis of cancer . Furthermore, gene dysregulation can lead to several other conditions such as autoimmune disease, inflammation, and obesity [12–14].
In normal cells regulatory mechanisms of gene expression usually include suppression of the expression of abnormal genes, but if this mechanism does not work properly it has to be intentionally regulated with the help of introduced exogenous factors, thus preventing the possible disease outcomes described above. To realize this goal, some studies have attempted to imitate a natural regulatory system in cells. For example, transcriptional inhibition can be achieved by inducing DNA methylation or supercoiling via exogenous inoculation of certain substances . In the case of translation inhibition, a variety of methods that inhibit the activation of translation factors have been proposed .
siRNA-based therapeutics in clinical trials.
Reproduced with permission 
Clinical trial ID
EUS biopsy needle
Pancreatic ductal adenocarcinoma
Solid tumors with liver involvement
National Cancer Inst.
Neuroendocrine tumors, adrenocortical carcinoma
Elevated LDL-cholesterol (LDL-C)
Elevated LDL-cholesterol (LDL-C)
ZEBOV L poly m., VP24, VP35
Ebola virus infection
Nitto Denko Corp.
Moderate to extensive hepatic fibrosis
Nitto Denko Corp.
Hemophilia A, hemophilia B
E3 ubiquitin ligase Cbl-b
Melanoma, pancreatic cancer, renal cell cancer
Wake Forest Univ.
Solid tumors, multiple myeloma, non-Hodgkin lymphoma
MD Anderson Cancer Center
With the rapid advancement of nanotechnology, a variety of nanomaterials that possess unique and excellent physicochemical properties not previously observed have been developed. Many have been exploited for practical and clinical uses in several biomedicine fields. For instance, the intrinsic characteristics of these materials are useful for the design of efficient therapeutic, diagnostic, and imaging agents [24–27]. In this short review, we focus more on progress and studies regarding nanomaterial-based cellular metabolic regulation in more detail, especially on gene regulatory systems based on newly designed nanomaterials.
In this review, we cover some representative nanomaterials including general nanoparticles, carbon-based materials, and polymer structures, concentrating on their characteristics and advantages and followed by addressing their limitations and providing perspectives for improvement in their gene-regulatory clinical applications.
2.1 General nanoparticles
The term nanoparticle commonly refers to an organic or inorganic particle with a size of 1–100 nm. Due to the rapid development of nanotechnology, nanoparticles can be easily manufactured with various sizes and shapes and even tailored with some functionalities for eventual use in several fields including medicine and food engineering [33–35]. Intracellular delivery of antagonist RNAs for gene regulation by RNA interference has mostly been achieved with the help of nanoparticle carriers. The surface of nanoparticles is pretreated with functional components that specifically recognize target cells and aid its intracellular entry while avoiding an immune response in the body .
Gold nanoparticles, which are simply abbreviated AuNPs, are widely used in bio-medical applications and have been demonstrated to have higher biocompatibility and lower cytotoxicity. Remarkably, AuNPs possess high absorbance at the wavelength of a specific visible light region and exhibit a photothermal effect with generation of heat when irradiated. Because of their unique optical properties they are widely used in both diagnostic and therapeutic systems . AuNPs can easily form a covalent bond with thiol derivatives and can therefore become tightly anchored with some genetic fragments without any complex modification processes .
Although AuNPs are directly used as a carrier for siRNA delivery, several studies have reported RNAi after a sustained and long-term release of siRNAs adhered onto the surface of nanoparticles by heat generated from AuNPs [40, 41]. As another example, AuNPs incorporating antisense sequences complementary to target mRNAs are internalized into cells, thus depleting mRNAs in the target cells . The reduced level of mRNAs was confirmed by tracking changes in emitted fluorescence. The data confirmed that the system could distinguish mRNAs very sensitively up to a single base difference and 92% of the target mRNAs could be removed .
2.2 Carbon-based materials
Single- and multi-walled carbon nanotubes, graphene, and carbon dots are the most commonly used carbon-based nanomaterials. Because of their higher biocompatibility and lower toxicity relative to other metal materials, they are suitable for several biomedical applications. In particular, they have been used in bioimaging or diagnostic applications due to their unique optical properties [50, 51]. Like AuNPs, they can emit heat through exposure to light radiation.
Furthermore, a ring structure of some carbon-based materials can easily form a non-covalent bond similar to a π–π stacking interaction between genes and carbon molecules. As a result of their high loading efficiency and simple loading process, they are able to effectively transfer genes into cells.
As in the previous example, a siRNA delivery system using graphene simultaneously detected the silencing of targeted genes as well as the efficiency of delivery of siRNAs through changes in fluorescence signals due to the quenching ability of graphene. Several similar systems have been developed .
2.3 Polymer-based materials
A polymer is a macromolecule in which one or more monomers are repeatedly associated. Polymers possess a wide variety of physical, chemical, electrical, and even optical properties depending on the characteristics of their constituent monomers, their dimensions, and synthesis environment, and can therefore be applied in nearly all academic and industrial fields. Polymers for biomedical uses are pretreated with other ingredients to change their surface charge or to impart specific functional groups. In many cases, polymers have high biocompatibility in the whole system, reducing their toxicity. They are also protected from immune responses or plasma degradation, which enhances their transfection efficiency into targeted cells .
In addition, polymers can be filled with certain drugs or effectors through chemical strategies of either covalent attachment or electrostatic attraction [58–60]. In recent years, biopolymers from the body and related synthetic polymer groups have been considered. Most interestingly, polysaccharide-based natural polymers represented by a chitosan and a hyaluronic acid are increasingly being focused on with respect to gene regulation. Zhou and colleagues  have synthesized nanoparticles composed of both hyaluronic acid and calcium phosphate. These nanoparticles carried siRNAs targeting Bcl2 genes and aided their cellular transport into melanoma. As a result, they silenced 85% of the targeted genes in vitro and even in vivo, resulting in dramatic apoptosis of targeted cancer cells. Another example of gene regulation using natural polymers has been developed by Yang and colleagues . A basic unit of the system used was a PCSK9 gene regulatory unit based on chitosan oligosaccharides (COS), a polymeric structure composed of N-acetyl-d-glucosamine and deacetylated glucosamine.
Cells possess mechanisms to control cellular gene expression and avert unpredicted expression of exogenous genes, thus maintaining normal metabolism. During the transcription process, the expression of gene transcripts is strictly regulated by DNA methylation, acetylation, or deacetylation. Such effects are also controlled by a variety of factors involved in transcription and translation processes. However, when the regulatory mechanism functions abnormally, cells may die or develop into malignant tumors through anomalous proliferation. In such cases, alternative gene regulatory strategies may be required. A method of inducing DNA methylation throughout the transcription process could be proposed. For the translation process, a method of obstructing the binding between mRNA and ribosome by interference with antisense RNAs could be envisioned. Since the discovery of RNAi by siRNA and miRNA, there have been many attempts to realize gene regulation by RNAi. As a result of their tremendous success, most recently developed gene regulation methods have been based on RNAi.
In addition, a variety of nanomaterials have been highlighted. With the rapid development of nanotechnology, several attempts to manipulate nanomaterials into functional moieties have been made to attain effective gene regulation. Most commonly, nanomaterials are used as a better vehicle to efficiently transport effector molecules for either DNA methylation or RNAi to targeted sites in the body. Several nanomaterials including inorganic and organic nanoparticles, carbon-based materials, and polymers have been explored. Relevant studies have mostly focused on efficient delivery of siRNA and antisense RNA for cancer treatment. The intrinsic physicochemical, electrical, and optical properties of the developed nanomaterials result in a higher transfection efficiency, yielding an efficient gene silencing effect.
In this review, we have briefly presented the most recent progress in gene regulation systems using advanced nanomaterials. In most cases, nanomaterials have been used as vehicles to deliver regulatory effectors such as siRNAs, although in some cases they have been directly applied for targeted gene regulation. Current gene regulation systems involving nanomaterials are predominantly focused on RNAi. However, RNAi has low variability and can only be designed for a single target mRNA, leading to incomplete knockdown in the whole system. In addition, siRNA is very vulnerable to external environments and is readily degraded within a short time. As a result, it requires a carrier or must be amended for protection. The need for a transfection agent may eventually reduce feasibility by greatly increasing the net cost of the system. To overcome these shortcomings, a novel gene regulation system is essential for better performance. Nanomaterial-based gene regulatory systems could represent an ideal alternative approach.
In the design of new gene regulatory materials, the following characteristics must be considered. First, either high target selectivity or universal availability is required. One of the reasons that RNA-based gene regulation methods such as siRNA or antisense RNA are attracting attention is because targeted mRNAs specifically react through complementary base hybridization. This not only improves the whole system efficiency by reducing possible off-target gene regulation, but also helps to reduce any side effects such as damage of exogenous DNAs. In addition, it is necessary to regulate many genes at the same time through only one single system. This will be an important characteristic for commercialization of the system by increasing the application in whole-system gene regulation while reducing the total price.
A number of studies have focused on AuNPs and CNTs, which are the most commonly used nanomaterials. However, these materials may cause random DNA methylation and catastrophic damage to targeted cells and genes [63, 64]. Non-specific toxicity to some normal cells and genes has been considered a critical drawback in biomedical applications, including gene regulation. In recent years, numerous efforts to overcome these problems have been attempted through surface modification, size variation, or combination with other materials. For effective and reliable regulation with acceptable safety, the non-specific toxicity of the nanomaterials must be addressed in ingenious ways.
The next generation of gene regulation systems must possess higher regulation efficiency. The RNA-based gene regulation systems developed to date have shown very effective silencing at the level of around 80–90% but have a relatively lower suppressive effect on mRNA compared with the corresponding protein expression. This may be ascribed to the effects of RNAi on the translation process; however, it results in incomplete removal of all mRNAs. Therefore, complete regulation at the transcriptional stage is required for effective gene regulation. This may require a more delicate design strategy for eukaryotic gene regulation because the nanomaterials must enter the nucleus where transcription occurs.
Gene regulatory effectors have evolved from a variety of smaller molecules to antisense RNA and RNAi molecules. There has also been significant progress in terms of transfection efficiency, gene regulation level, and duration. Currently, RNAi-based gene regulation using siRNA is predominantly used, but there are still many drawbacks that must be overcome as described above. Nanomaterials have unique physico-chemical properties, and it is relatively easy to manipulate their size, shape, and surface properties. Therefore, a gene regulation strategy using nanomaterials may be an answer to the next generation of upgraded gene regulation systems that complement the advantages of existing methods. To this end, it is necessary to overcome the above-mentioned disadvantages while moving forward with optimizing the required characteristics.
SHC, JSY, SHU searched and collected references and information. They have established the whole manuscript and managed the figures and their captions. All authors have written and reviewed the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant No. HI16C1984) and by grants from Basic Science Research Programs through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (Grant No. 2016R1D1A1B03931270).
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