DNA hydrogel-based gene editing and drug delivery systems
Graphical abstract
Introduction
Deoxyribonucleic acid (DNA) is the gift of the nature, consisting of just four types of monomeric nucleotides, yet carrying substantial genetic information of almost all life. The combination of Watson-Crick base pairing and DNA synthesis technology has facilitated DNA applications in materials design [1,2]. In the 1980s, the cross-shaped DNA structure, instead of the regular linear DNA double helix, was first designed via predictive sequence-directed hybridization by Seeman [3]. Afterwards, the field of DNA nanotechnology progressed rapidly [4,5]. Remarkably, in 1996, Nagahara and Matsuda designed the first DNA-based hydrogel via the crosslinking of single-stranded (ss) DNA grafted on polyacrylamide chains [6]. DNA hydrogels are 3-D hydrophilic networks that feature DNA as a component and can absorb water and swell in aqueous solution. According to their composition, DNA hydrogels are classified as either pure or hybrid [7], and both can be formed by physical self-assembly or chemical crosslinking. By different design principles, DNA hydrogels in a variety of sizes including bulk hydrogels, micro- and nanogels have been developed [8]. For example, DNA nanogels are particulate hydrogels with dimensions of nanometers, which combine DNA hydrogels with the advantages of nano-scale particles. Since the DNA strands are programmable, complementary and chemically modifiable, they can be manipulated flexibly to form various DNA building blocks with unique geometries, resulting in a highly predictable and structured DNA network. Also, 3D scaffolds within DNA hydrogels afford mechanical rigidity and offer plenty of conjugation sites, thereby boosting their functionality as stable immobilization matrices for tethering nanoparticles (NPs) or molecular components. The physicochemical stability of “smart hydrogels” changes in response to surrounding environmental triggers. Consequently, these constructs have received additional research attention in the biosensing and biomedical fields [9,10]. Apart from nonbiological stimuli as mediators of responsiveness, DNA hydrogels further expand the available stimuli to biological stimuli [11]. Based on the structural and functional information encoded on DNA crosslinkers, DNA hydrogels can be triggered by a variety of biomolecules, including glucose, adenosine triphosphate (ATP), nucleic acids (NAs), and enzymes [[12], [13], [14]]. Obviously, many other hydrogels developed from natural sources, such as gelatin and alginate, lack structural programmability [15]. Therefore, DNA hydrogels with customized features are favored in biological applications.
Interest is growing in the application of DNA-based hydrogels as a vehicle for drug delivery. Traditional drug administration often requires frequent administration or high drug dosage to realize therapeutic efficacy. It is often accompanied by systemic adverse reaction, thus lowering overall effects and patient compliance [16,17]. The emergence of immunotherapy and gene therapy [[18], [19], [20]], which involves functional biomolecules of DNA, RNA and proteins, has presented new challenges for in vivo drug delivery. Naked nucleic acids and proteins have short serum half-lives because they are susceptible to enzymatic degradation, and cell transfection efficiency is also very poor [20,21]. Additionally, the biological activity of protein is easily damaged during carrier encapsulation. Therefore, it is essential to engineer active and effective carriers for controllable delivery of small-molecule and biomolecule drugs. A broad range of carriers, such as inorganic NPs [22], polymers [23], proteins [24] and liposomes [25], have been reported. Although their intrinsic nature has improved treatment efficacy, carrier-induced problems of immunogenicity, nonspecific drug leakage and difficult biodegradability are still obstacles to complete efficiency [[25], [26], [27]]. Given the excellent biocompatibility, tunable mechanical properties, controlled phase transformation as well as simple preparation, DNA hydrogels have showed a bright prospect as the suitable vehicles. In addition to the achievement of in situ encapsulation of drugs, DNA hydrogels also allow the establishment of molecular recognition with target region and an integration of multiple components for synergistic treatment [28].
We conduct this review in three steps, first summarizing the basic design and synthesis principles of DNA hydrogels, then introducing the stimuli responsiveness of smart DNA hydrogels, and finally highlighting DNA hydrogel-based drug delivery platforms, to include the delivery of biomacromolecules in immunotherapy, gene therapy and combination therapy.
Section snippets
Design and synthesis
The design and synthesis of DNA hydrogels affect their yield and subsequent performance in biological applications [29]. In general, DNA hydrogels are formed by chemical and physical crosslinking. Chemical crosslinking refers to the intermolecular covalent interactions of linear DNA-DNA or DNA-polymer, which usually requires laborious steps of synthesis and the addition of chemical crosslinking reagents [30]. The prominent advantage of chemical crosslinking is that it can form permanent and
Stimuli-responsive DNA hydrogels
The development of stimuli-responsive smart DNA hydrogels has attracted widespread research interest. Stimuli-responsive DNA hydrogels can respond to external triggers and then change their phase property or crosslinking density accordingly [49]. In DNA hydrogel-based delivery systems, responsive behaviors can drive the controlled targeting, accumulation of payloads and on-demand release, which can improve therapeutic profiles and decrease side effects. A variety of triggers can induce
DNA-based hydrogel in drug delivery
A successful drug delivery platform should possess several properties, including preservation of the intact bioactivity of drugs and prevention of chemical and enzymatic degradation; proper size to reduce blood clearance and the ability to cross biological barriers and enhancement of retention effect; elimination of unpleasant features, like poor solubility, immunogenicity, toxicity and drug resistance; and, finally, smart delivery for specific targeting and controllable release kinetics.
DNA
Conclusions and outlook
The interdisciplinary integration between biochemistry and materials science has motivated the evolution of diverse biocompatible materials for biosensing and biomedical applications. With the properties of hydrophilicity, softness, predictable structure, automated synthesis, high encapsulation efficiency, stimuli responsiveness and capability of molecular recognition, DNA hydrogels have been used for all kinds of elegant drug delivery systems. Although studies reporting on the fabrication and
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
The authors are grateful for financial support from the National Natural Science Foundation of China (Grant No. 81822024, 11761141006 and 21605102), the National Key Research and Development Program of China (Grant No. 2017YFC1200904), and the Natural Science Foundation of Shanghai (Grant No. 19520714100 and 19ZR1475800).
References (194)
- et al.
Recent advances in DNA nanotechnology
Curr. Opin. Chem. Biol.
(2018) Nucleic acid junctions and lattices
J. Theor. Biol.
(1982)- et al.
Hydrogel formation via hybridization of oligonucleotides derivatized in water-soluble vinyl polymers
Polymer. Gels Networks
(1996) - et al.
Endonuclease-responsive aptamer-functionalized hydrogel coating for sequential catch and release of cancer cells
Biomaterials
(2013) - et al.
Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer
Biomaterials
(2015) - et al.
Liposomal drug delivery systems: from concept to clinical applications
Adv. Drug Deliv. Rev.
(2013) Polymeric nanoparticles for targeted drug delivery system for cancer therapy
Mater. Sci. Eng. C Mater. Biol. Appl.
(2016)- et al.
Thermoresponsive hydrogels in biomedical applications
Eur. J. Pharm. Biopharm.
(2008) - et al.
Thermosensitive sol-gel reversible hydrogels
Adv. Drug Deliv. Rev.
(2002) - et al.
Environment-sensitive hydrogels for drug delivery
Adv. Drug Deliv. Rev.
(2012)
Cas9-edited immune checkpoint blockade PD-1 DNA polyaptamer hydrogel for cancer immunotherapy
Biomaterials
SELEX—a (r)evolutionary method to generate high-affinity nucleic acid ligands
Biomol. Eng.
Nanogels: an overview of properties, biomedical applications and obstacles to clinical translation
J. Control. Release
Gold nanocage decorated pH-sensitive micelle for highly effective photothermo-chemotherapy and photoacoustic imaging
Acta Biomater.
Carbon dots assisted formation of DNA hydrogel for sustained release of drug
Carbon
Multifunctional quantum dot DNA hydrogels
Nat. Commun.
The discovery of hydrogen bonds in DNA and a re-evaluation of the 1948 Creeth two-chain model for its structure
Biochem. Soc. Trans.
Evolution of structural DNA nanotechnology
Adv. Mater.
From DNA nanotechnology to material systems engineering
Adv. Mater.
Functional nucleic acid-based hydrogels for bioanalytical and biomedical applications
Chem. Soc. Rev.
DNA hydrogels and microgels for biosensing and biomedical applications
Adv. Mater.
Bioresponsive hydrogels: chemical strategies and perspectives in tissue engineering
Gels
Modular design of programmable mechanofluorescent DNA hydrogels
Nat. Commun.
Bioresponsive DNA hydrogels: beyond the conventional stimuli responsiveness
Acc. Chem. Res.
DNA-responsive SiO2 nanoparticles, metal-organic frameworks, and microcapsules for controlled drug release
Langmuir
A triggered DNA hydrogel cover to envelop and release single cells
Adv. Mater.
Biomedical applications of DNA-based hydrogels
Adv. Funct. Mater.
A concise review on smart polymers for controlled drug release
Drug Deliv. Transl. Res.
From conventional chemotherapy to targeted therapy: use of monoclonal antibodies (moAbs) in gastrointestinal (GI) tumors
Tumour Biol.
Immunotherapeutic uses of CpG oligodeoxynucleotides
Nat. Rev. Immunol.
Immunotherapy and gene therapy as novel treatments for cancer
Colomb. Med. (Cali.)
Non-viral vectors for gene-based therapy
Nat. Rev. Genet.
Precision cancer theranostic platform by in situ polymerization in perylene diimide-hybridized hollow mesoporous organosilica nanoparticles
J. Am. Chem. Soc.
In vivo environment-adaptive nanocomplex with tumor cell-specific cytotoxicity enhances T cells infiltration and improves cancer therapy
Small
Simple in vivo gene editing via direct self-assembly of Cas9 ribonucleoprotein complexes for cancer treatment
ACS Nano
Topical drug delivery systems: a patent review
Expert Opin. Ther. Pat.
Nucleic acid-based functional nanomaterials as advanced cancer therapeutics
Small
Engineering DNA-based functional materials
Chem. Soc. Rev.
DNA hydrogel assemblies: bridging synthesis principles to biomedical applications
Adv. Ther.
Advances in crosslinking strategies of biomedical hydrogels
Biomater. Sci.
Designing hydrogels for controlled drug delivery
Nat. Rev. Mater.
Enzyme-catalysed assembly of DNA hydrogel
Nat. Mater.
Controlled trapping and release of quantum dots in a DNA-switchable hydrogel
Small
pH- and ligand-induced release of loads from DNA-acrylamide hydrogel microcapsules
Chem. Sci.
DNA sequence-directed shape change of photopatterned hydrogels via high-degree swelling
Science
pH-stimulated DNA hydrogels exhibiting shape-memory properties
Adv. Mater.
Photocrosslinked DNA nanospheres for drug delivery
Macromol. Rapid Commun.
A mechanical metamaterial made from a DNA hydrogel
Nat. Nanotechnol.
Programmable DNA Hydrogels Assembled from Multidomain DNA Strands
Chembiochem
DNA/tannic acid hybrid gel exhibiting biodegradability, extensibility, tissue adhesiveness, and hemostatic ability
Adv. Funct. Mater.
Cited by (148)
Remodelers of the vascular microenvironment: The effect of biopolymeric hydrogels on vascular diseases
2024, International Journal of Biological MacromoleculesAI energized hydrogel design, optimization and application in biomedicine
2024, Materials Today BioBiomedical applications of stimuli-responsive “smart” interpenetrating polymer network hydrogels
2024, Materials Today BioActively targeted and dual-stimuli-responsive branch-shaped system for simultaneous microRNAs imaging in living cells
2024, Sensors and Actuators B: Chemical