Elsevier

Advanced Drug Delivery Reviews

Volume 168, January 2021, Pages 79-98
Advanced Drug Delivery Reviews

DNA hydrogel-based gene editing and drug delivery systems

https://doi.org/10.1016/j.addr.2020.07.018Get rights and content

Abstract

Deoxyribonucleic acid (DNA) is a promising synthesizer for precisely constructing almost arbitrary geometry in two and three dimensions. Among various DNA-based soft materials, DNA hydrogels are comprised of hydrophilic polymeric networks of crosslinked DNA chains. For their properties of biocompatibility, porosity, sequence programmability and tunable multifunctionality, DNA hydrogels have been widely studied in bioanalysis and biomedicine. In this review, recent developments in DNA hydrogels and their applications in drug delivery systems are highlighted. First, physical and chemical crosslinking methods for constructing DNA hydrogels are introduced. Subsequently, responses of DNA hydrogels to nonbiological and biological stimuli are described. Finally, DNA hydrogel-based delivery platforms for different types of drugs are detailed. With the emergence of gene therapy, this review also gives future prospects for combining DNA hydrogels with the gene editing toolbox.

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).

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