# Mechanical Properties of DNA Hydrogels: Towards Highly Programmable Biomaterials
## 1 Introduction  
Deoxyribonucleic acid (DNA) nanotechnology uses DNA molecules as a building block to assemble various types of nanoscale architectures [1; 2; 3]. Considerable progress has been made in the DNA nanotechnology field in only a few decades, and now DNA is routinely used to synthetize complex one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) nanostructures [4; 5; 6; 7; 8], meshes [9; 10], devices [11; 12; 13], and hybrid biomaterials [14; 15; 16; 17], among others. These DNA architectures can be assembled using different techniques such as tile assembly [18; 19], DNA origami [4], and DNA bricks [20]. DNA-based materials are developing rapidly because of the unique structural, mechanical, and biochemical features offered by DNA building blocks that are not found in any other polymeric materials. For instance, DNA-based assembly relies on the Watson-Crick base pairing mechanism to hybridize two single strands of DNA (ssDNA) with complementary sequences and form double stranded DNA (dsDNA) molecules, thus making DNA-based materials highly programmable, which allows for high specificity of assembly at the nanoscale using simple sequence design. The structural predictability provides the user with modeling capability and an exquisite control over the final assembly as well as great design flexibility [4; 7; 19; 21]. In addition, the mechanical properties of DNA-based nanoarchitectures can be easily programmed by changing the type of DNA motifs used, the hybridization state, and their nanostructure design [22; 23; 24; 25; 26]. DNA materials are inherently biocompatible, self-assemble in solution, exhibit high structural stability, and their ease of modification makes them a great material to scaffold various organic and inorganic molecules with nanoscale precision to functionalize the nanoarchitectures [27; 28; 29; 30]. While DNA building blocks have been used extensively to assemble several nanoscale objects, DNA as a material is now gaining more traction as a potential candidate for larger scale polymeric biomaterials assembly, particularly to build nanostructured functional soft hydrogels with sizes ranging from the nanoscale to the millimeter scale. Similar to the discrete DNA nanostructures, the structural, mechanical, and biochemical properties of these DNA hydrogels are highly controllable [31; 32; 33]. In the past decade, several studies have demonstrated the potential of these DNA hydrogels to be used in several biomedical applications [34] including drug delivery [35; 36; 37], cancer therapy [38; 39; 40], antigen delivery and immunomodulation [41; 42], sensing [43; 44; 45], and extracellular matrix (ECM) mimics for tissue engineering [34; 46]. In addition, using the unique biochemical properties of DNA, pure and hybrid DNA hydrogels can be designed to be responsive to specific stimuli, such as pH, temperature, biomolecules, and strand displacement [38; 47; 48]. For instance, introducing pH-sensitive crosslink motifs such as the i-motif or the G-quadruplex inside the DNA hydrogel design has been used to control the stiffness of DNA-based hydrogels [31; 49]. Careful sequence design of the linker or the hydrogel motifs allows for precisely controlling the melting temperature and the mechanical properties. Several methods are also available to induce DNA hydrogel crosslinking in order to control the structural stability and the mechanical properties of the hydrogels [38; 47; 50]. Thus, their mechanical, structural, and biochemical properties can be modulated in real time, which represents an immense advantage over other types of polymeric hydrogels that are static by nature. This review focuses on the different methods used to assemble DNA hydrogels and the various designs used to control their mechanical properties. Particularly, it focuses on the crosslinking methods used and the relationship between the structure and the mechanical properties of the DNA-based hydrogels.