Recent Advances of DNA Hydrogels in Biomedical Applications

DNA hydrogel is one of DNA-based nanomaterials with unique advantages such as precise self-assembly,programmability,addressability,high stability,excellent biocompatibility and biodegradability,and tunable versatility.These features have greatly promoted the development of DNA hydrogels in various applications,especially molecular diagnostics,biosensing,drug delivery,and cancer therapy.In this review,we briefly review the history of DNA hydrogels,the latest advances of DNA hydrogels in biomedical applications especially in biosensing,drug delivery and cancer therapy,and prospect the key challenges and future directions.

DNA-based supramolecular hydrogels:From construction strategies to biomedical applications

DNA-based supramolecular hydrogels are important and promising biomaterials for various applications due to their inherent biocompatibility and tunable physicochemical properties.The three-dimensional supramolecular matrix of DNA formed by non-covalently dynamic cross-linking provides exceptional adaptability,self-healing,injectable and responsive properties for hydrogels.In addition,DNA hydrogels are also ideal bio-scaffold materials owing to their tissue-like mechanics and intrinsic biological functions.Technically,DNA can assemble into supramolecular networks by pure complementary base pairing;it can also be combined with other building blocks to construct hybrid hydrogels.This review focuses on the development and construction strategies of DNA hydrogels.Assembly and synthesis methods,diverse responsiveness and biomedical applications are summarized.Finally,the challenges and prospects of DNA-based supramolecular hydrogels are discussed.

Preparation of Photo-responsive DNA Supramolecular Hydrogels and Their Application as UV Radiometers

Ultraviolet light(UV)is an essential component of ambient light,but high dose UV would damage genome DNA.While semiconductors and soft materials have been employed to detect the UV,the complex process and the instrumental requirement have limited the application in daily life.In this study,taking advantage of sequence designability,a series of hydrogels with different gel-sol transition rates was constructed under the same UV intensity by introducing competing hybridization to tune the stability of the molecular network.Through estimating the transition time between each system under UV light irradiation,the intensity of UV could be roughly estimated,which provided a convenient method for the visual detection of UV.

Black phosphorus nanosheets-enabled DNA hydrogel integrating 3D-printed scaffold for promoting vascularized bone regeneration

The classical 3D-printed scaffolds have attracted enormous interests in bone regeneration due to the customized structural and mechanical adaptability to bone defects.However,the pristine scaffolds still suffer from the absence of dynamic and bioactive microenvironment that is analogous to natural extracellular matrix(ECM)to regulate cell behaviour and promote tissue regeneration.To address this challenge,we develop a black phosphorus nanosheets-enabled dynamic DNA hydrogel to integrate with 3D-printed scaffold to build a bioactive gel-scaffold construct to achieve enhanced angiogenesis and bone regeneration.The black phosphorus nanosheets reinforce the mechanical strength of dynamic self-healable hydrogel and endow the gel-scaffold construct with preserved protein binding to achieve sustainable delivery of growth factor.We further explore the effects of this activated construct on both human umbilical vein endothelial cells(HUVECs)and mesenchymal stem cells(MSCs)as well as in a critical-sized rat cranial defect model.The results confirm that the gel-scaffold construct is able to promote the growth of mature blood vessels as well as induce osteogenesis to promote new bone formation,indicating that the strategy of nano-enabled dynamic hydrogel integrated with 3D-printed scaffold holds great promise for bone tissue engineering.

Lanthanide-DNA supramolecular hydrogels with tunable and responsive luminescence

Supramolecular DNA hydrogels have been synthesized based on the assembly of DNA building-blocks such as branched DNA and long DNA chains.The structures and functions of sole-module DNA hydrogels remain limitations.New methodologies by integrating hybrid components are desired to expand the synthesis of DNA hydrogel.Herein,we synthesized a Ln^(3+)-containing luminescent supramolecular hydrogel by employing the coordination and electrostatic interactions between lanthanide ions(Tb^(3+)and Eu^(3+))and linear single-stranded DNA(ssDNA).Through the coordination between ssDNA and Ln^(3+),a series of luminescent supramolecular hydrogels were synthesized,among which the Tb-G_(n)/T_(n)and Eu-T_(n)hydrogels emitted the characteristic luminescence of Tb and Eu,respectively.The luminescent intensities of the hydrogels were adjusted by designing DNA sequences with programmable bases and chain lengths.Notably,the Tb/Eu co-doped luminescent supramolecular hydrogel displayed tunable luminescence from green to yellow by regulating the stoichiometric ratio of Tb/Eu.Moreover,the hydrogel had reversible luminescent stimulation responsiveness toward Ag^(+)/L-Cys.We expected that the synthesis of Ln^(3+)-containing luminescent supramolecular hydrogels enriched the strategies of the construction of DNA hydrogels,and promoted the development of stimuli-responsive supramolecular materials.

Supramolecular G-quadruplex hydrogels:Bridging fabrication to biomedical application

G-quadruplex hydrogel is a class of self-assembled supramolecular hydrogel formed by guanine derivatives.As a biomimetic hydrogel,G-quadruplex hydrogels demonstrate wide biomedical applications,such as drug delivery,tissue engineering,and biosensing.The advantages of using G-quadruplex hydrogels include adequate biocompatibility and biodegradability,tunable multifunctionality,and cost-effective and large-scalable fabrication process.In this review,we focus on recent progress in the fabrication and characterization of G-quadruplex hydrogels to help readers understand the principles of G-quadruplex hydrogel formation.Meanwhile,the applications of G-quadruplex hydrogels in the biomedical area are discussed,aiming to pave the way for downward clinical or industry translation.The development of G-quadruplex hydrogel is still in its infancy.We hope this review will boost the development of this area and that more applications of G-quadruplex hydrogel will be developed.

Fabrication of nanozyme@DNA hydrogel and its application in biomedical analysis

Nanozymes have received great attention owing to the advantages of easy preparation and low cost. Unlike natural enzymes that readily adapt to physiological environments, artificial nanozymes are apt to passivate in complex clinical samples （e.g., serum）, which may damage the catalytic capability and consequently limit the application in biomedical analysis. To conquer this problem, in this study, we fabricated novel nanozyme@DNA hydrogel architecture by incorporat^ng nanozymes into a pure DNA hydrogel. Gold nanoparticles （AuNPs） were adopted as a model nanozyme. Results indicate that AuNPs incorporated in the DNA hydrogel retain their catalytic capability in serum as they are protected by the hydrogel, whereas AuNPs alone totally lose the catalytic capability in serum. The detection of hydrogen peroxide and glucose in serum based on the catalysis of the AuNPs@DNA hydrogel was achieved. The detection limit of each reaches 1.7 and 38 ~M, respectively, which is equal to the value obtained using natural enzymes. Besides the mechanisms, some other advantages, such as recyclability and availability, have also been explored. This nanozyme@DNA hydrogel architecture may have a great potential for the utilization of nanozymes as well as the application of nanozymes for biomedical analysis in complex physiological samples.

Rapid Shape Memory and p H-modulated Spontaneous Actuation of Dopamine Containing Hydrogels

The dopamine containing hydrogels with rapid responsive shape memory capability were synthesized by a one-pot method. The temporary shape of hydrogel was fixed within 20 s in Na OH solution by the tris-complex crosslinking of metalligand complex between Fe3＋ ions and catechol groups, while the permanent shape was recovered completely in HCl solution within 60 s upon the change from tris-complex to mono-complex. The hydrogel showed unique spontaneous actuation behavior. It could curl spontaneously without further external force deformation when immersed in Na OH solution again after the first shape recovery in HCl solution. This might be attributed to the competitive result of swelling and additional tris-complex crosslinking formation when immersed in Na OH solution. In addition, the hydrogels also had proper modulus, elongation ratio and tensile strength. Such hydrogel provides a new candidate material for designing soft actuators and robots modulated with spontaneous actuating.

Light-Mediated Spatiotemporally Dynamic Assembly of DNA Nanostructures in Living Cells Regulates Autophagy

The assembly of exogenous artificial architectures inside cells can regulate a series of biological events,which heavily relies on the development of spatiotemporally controlled molecular assembly systems.We herein report a designer deoxyribonucleic acid(DNA)nanostructure that enables light-mediated spatiotemporally dynamic assembly in living cells and consequently achieves efficient regulation of cell autophagy.The DNA nanostructure was constructed from i-motif moiety-containing branched DNA,photocleavable bond-containing linker,and tumor cell-targeting aptamer.After cellular uptake mediated by aptamers,under the spatiotemporal control of both UV light and late endosomal/lysosomal acidic environments,disassembly/reassembly of DNA nanostructure occurred via two rationally designed routes,generating microsized DNA assembly.As a result,autophagy was significantly enhanced with the increase of DNA assembly size.The enhanced autophagy showed an impact on related biological effects.Our system is expected to be a powerful tool for the regulation of intracellular events and cellular behaviors.