Small Molecule‐Templated DNA Hydrogel with Record Stiffness Integrates and Releases DNA Nanostructures and Gene Silencing Nucleic Acids

Abstract

Deoxyribonucleic acid (DNA) hydrogels are a unique class of programmable, biocompatible materials able to respond to complex stimuli, making them valuable in drug delivery, analyte detection, cell growth, and shape-memory materials. However, unmodified DNA hydrogels in the literature are very soft, rarely reaching a storage modulus of 10 3 Pa, and they lack functionality, limiting their applications. Here, a DNA/small-molecule motif to create stiff hydrogels from unmodified DNA, reaching 10 5 Pa in storage modulus is used. The motif consists of an interaction between polyadenine and cyanuric acid-which has 3-thymine like faces-into multimicrometer supramolecular fibers. The mechanical properties of these hydrogels are readily tuned, they are self-healing and thixotropic. They integrate a high density of small, nontoxic molecules, and are functionalized simply by varying the molecule sidechain. They respond to three independent stimuli, including a small molecule stimulus. These stimuli are used to integrate and release DNA wireframe and DNA origami nanostructures within the hydrogel. The hydrogel is applied as an injectable delivery vector, releasing an antisense oligonucleotide in cells, and increasing its gene silencing efficacy. This work provides tunable, stimuli-responsive, exceptionally stiff all-DNA hydrogels from simple sequences, extending these materials' capabilities.

Rational Design of DNA Hydrogels Based on Molecular Dynamics of Polymers

“…[ 17 ] By introducing a half i ‐motif domain crosslink the polymerized DNA DX backbone, DNA hydrogel could form under ultralow gelation concentration (2 m m ), and the high rigidity of DX polymer backbone endowed the hydrogel with high mechanical stiffness, nearly 20 times larger than of the hydrogel with dsDNA backbone. Recently, a rigid triple helix DNA fiber composed of polydeoxyadenine and cyanuric acid (CA), a small nontoxic molecule, has been employed as backbone for the fabrication of DNA hydrogels with a significant stiffness of 10 4 Pa. [ 40 ] Furthermore, substituting CA molecules with positively charged CAC2NH 2 could lead to more rigid backbones. As a result, the storage modulus of the DNA hydrogel could be further enhanced to 10 5 Pa at only 4.7 wt%, which was two orders of magnitude higher than most of the reported DNA hydrogels.…”

“…Nucleic acid drugs, such as antisense oligonucleotides (ASOs), [ 40 ] small interfering RNAs (siRNAs), [ 158 ] microRNA, [ 159 ] and messenger RNA (mRNA) [ 160 ] can also be enclosed in DNA hydrogels in a facile way. [ 161 ] A DNA‐RNA hybrid hydrogel was created to act as a matrix with siRNA delivery components that targeted tumors (Figure 14b).…”

“…Furthermore, various other therapeutic substances, such as metformin (MET) for blood sugar reduction, [154] borneol for pain and itch relief, [155] and procyanidin B2 (OPC B2) for antioxidant properties, [156] were successfully encapsulated within DNA hydrogels, highlighting the versatility of this platform for drug delivery. [157] Nucleic acid drugs, such as antisense oligonucleotides (ASOs), [40] small interfering RNAs (siRNAs), [158] microRNA, [159] and messenger RNA (mRNA) [160] can also be enclosed in DNA hydrogels in a facile way. [161] A DNA-RNA hybrid hydrogel was created to act as a matrix with siRNA delivery components that targeted tumors (Figure 14b).…”

Cobalt-Adenosine Monophosphate Supramolecular Hydrogel with pH-Responsive Multi-Nanozymatic Activity

“…In this regard, low-molecular-weight biomolecules are a prominent choice as the organic component due to their inherent properties such as common availability, low cost, and biocompatibility. Several biomolecules, such as peptides, urea- and amide-based molecules, sugar-based derivatives, and nucleobases, have been exploited as organic ligands to coordinate with metal ions to form supramolecular metallogels. − …”

Beyond nature's base pairs: machine learning-enabled design of DNA-stabilized silver nanoclusters

“…Through this case study, this Feature Article intends to provide researchers within the field of materials chemistry with insights into how ML and data mining can be successfully harnessed for advancing both discovery and fundamental chemical understanding of materials systems. In particular, the approaches and models discussed are highly promising for nucleic acid-based materials [33][34][35][36] and other systems whose properties are governed by biomolecular sequence, such as peptide-and protein-based materials. [37][38][39][40] 2 Fundamentals of nucleic acidstabilized metal nanoclusters It has been known that Ag + has affinity for the nucleobases but not the phosphate backbone of natural DNA at neutral pH.…”