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= DNA Nanogel Drug Delivery = DNA nanogels are an emerging technology in the field of drug delivery. DNA nanogels fall under the larger umbrella of nanogel drug delivery and are being investigated for their ability to change from many stimuli. The technology is being investigated for its potential as a delivery method for cancer therapy.

Overview of Nanogels
Nanogels are a technology being investigated as a potential delivery vehicle for therapeutics. There are many routes for the delivery of nanogels, including oral, pulmonary, and topical. Additionally, there are quite a few properties of nanogels. The materials used for the technology make it both biocompatible and biodegradable. Nanogels are also able to swell or shrink depending on the environment they are placed in. There are functional units within the nanogel that can be beneficial in its drug-carrying and drug-releasing properties. This form of drug delivery has a size between 20-200 nm, making it to large for uptake in the renal system but small enough to cross the blood brain barrier. In addition, nanogels usually do not induce any immunological responses. On the other hand, there are a few disadvantages to nanogels. A step in fabrication involves removing solvents and surfactants which can be costly. Moreover, if the surfactants are not completely removed, there can be some cytotoxic effects.

There are a few ways to classify nanogels. They are typically grouped by the linkages made during fabrication and the gel’s responsive behavior. The two ways gels are crosslinked chemically or physically. Additionally, nanogels are categorized on their ability to respond to their environment. There are non-responsive nanogels that only swell and shrink depending on the water content of the environment. There are also gels that can respond to environmental factors such as pH or light.

Fabrication Methods
Generally, DNA nanogels are made through chemical and physical crosslinking. Chemical crosslinking is a labor-intensive process that involves the covalent linking between pieces of DNA or the DNA to the polymer. This process also usually involves some reagent to make crosslinking possible. Physical crosslinking involves noncovalent linking such as hydrogen bonding between complementary pairs within DNA strands or electrostatic interactions between DNA and electrolytes.

Chemical Crosslinking
Chemical crosslinking is usually achieved using copolymerization, enzyme-driven, or light-driven linkages. Hybrid DNA gels are made through covalent crosslinking between the DNA and the polymer. A commonly used polymer for these hybrid gels is polyacrylamide (PAAm). Two modified DNA chains get copolymerized to acrylamide, creating DNA-PAAm chains. These chains are then mixed and networks are formed by adding complementary DNA. Enzyme-catalyzed crosslinking can be used to link DNA via T4 ligase, resulting in a pure DNA hydrogel. Light-driven linkages are created using photoreactive groups at the end of DNA fragments. These fragments connect when exposed to UV light, forming linked nanospheres. One major advantage of chemically crosslinked DNA nanogels is their stability. This is due to the irreversible bonds formed during fabrication.

Physical Crosslinking
Physical crosslinking of DNA nanogels is usually completed by exploiting some of the interactions seen in DNA, such as the complementary nature of nucleic acids. Cationic electrolytes can also have electrostatic interactions with DNA to crosslink fragments. Physical crosslinked DNA nanogels have reversible bonds. As a result, they are not as stable as chemically crosslinked gels. However, they tend to exhibit better biocompatibility and degradability. Additionally, there is a lesser concern for cytotoxicity since there are no reagents that need to be removed.

Stimulus Responses
There have been recent investigations into the use of stimuli-responsive DNA nanogels. When in contact with a particular stimulus, the gel can change crosslinking density or phase property. Stimuli can be divided into two categories: nonbiological and biological. A few examples of nonbiological stimuli include light, pH, and temperature. Temperature is the most common stimulus used for hydrogels. When the ambient temperature gets higher than the melting temperature of DNA, the DNA complex will change from a gel to a solution, allowing for drug release. Additionally, light can be used as a stimulus to form the DNA duplex while UV lights break the DNA linkage. Biological stimuli consist of biomolecules such as enzymes or ATP. The main principle for using biological stimuli relies on recognition of molecules such as DNA-DNA, ribonucleoprotein-DNA, and enzyme-substrate.

Applications
DNA nanogels as a drug delivery method have many advantages that can be exploited for use in chemotherapy, immunotherapy, and gene therapy. In gene therapy, it is very important that the therapy is target specific. Therefore, using a DNA nanogel could prove to be useful. With how easy it is to modify a DNA nanogel, the therapeutic can be delivered to the site efficiently with minimal off-target effects in combination with the use of CRISPR/Cas.

Limitations
There are a few limitations regarding DNA nanogels before they can become commercially available. One main hindrance is being able to effectively scale up the technology in a cost-effective manner without compromising quality. Additionally, this is still a very new technology, so many in vivo studies must be conducted before it can be ready for human clinical trials. This is because there is still much to investigate regarding the pharmacokinetics of DNA nanogels. Since there have not been any studies done on humans it is hard to tell if there are any immunological concerns for humans with this technology.