Rational Design of DNA Hydrogels Based on Molecular Dynamics of Polymers.

In recent years, DNA has emerged as a fascinating building material to engineer hydrogel due to its excellent programmability, which has gained considerable attention in biomedical applications. Understanding the structure-property relationship and underlying molecular determinants of DNA hydrogel is essential to precisely tailor its macroscopic properties at molecular level. In this review, the rational design principles of DNA molecular networks based on molecular dynamics of polymers on the temporal scale, which can be engineered via the backbone rigidity and crosslinking kinetics, are highlighted. By elucidating the underlying molecular mechanisms and theories, it is aimed to provide a comprehensive overview of how the tunable DNA backbone rigidity and the crosslinking kinetics lead to desirable macroscopic properties of DNA hydrogels, including mechanical properties, diffusive permeability, swelling behaviors, and dynamic features. Furthermore, it is also discussed how the tunable macroscopic properties make DNA hydrogels promising candidates for biomedical applications, such as cell culture, tissue engineering, bio-sensing, and drug delivery.

Dissecting the intricacies of human antibody responses to SARS-CoV-1 and SARS-CoV-2 infection.

The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV-1) causes more severe disease than SARS-CoV-2, which is responsible for COVID-19. However, our understanding of antibody response to SARS-CoV-1 infection remains incomplete. Herein, we studied the antibody responses in 25 SARS-CoV-1 convalescent patients. Plasma neutralization was higher and lasted longer in SARS-CoV-1 patients than in severe SARS-CoV-2 patients. Among 77 monoclonal antibodies (mAbs) isolated, 60 targeted the receptor-binding domain (RBD) and formed 7 groups (RBD-1 to RBD-7) based on their distinct binding and structural profiles. Notably, RBD-7 antibodies bound to a unique RBD region interfaced with the N-terminal domain of the neighboring protomer (NTD proximal) and were more prevalent in SARS-CoV-1 patients. Broadly neutralizing antibodies for SARS-CoV-1, SARS-CoV-2, and bat and pangolin coronaviruses were also identified. These results provide further insights into the antibody response to SARS-CoV-1 and inform the design of more effective strategies against diverse human and animal coronaviruses.

Effects of Univariate Stiffness and Degradation of DNA Hydrogels on the Transcriptomics of Neural Progenitor Cells.

Mechanical interactions between cells and extracellular matrix (ECM) are critical for stem cell fate decision. Synthetic models of ECM, such as hydrogels, can be used to precisely manipulate the mechanical properties of the cell niche and investigate how mechanical signals regulate the cell behavior. However, it has long been a great challenge to tune solely the ECM-mimic hydrogels' mechanical signals since altering the mechanical properties of most materials is usually accompanied by chemical and topological changes. Here, we employ DNA and its enantiomers to prepare a series of hydrogels with univariate stiffness regulation, which enables a precise interpretation of the fate decision of neural progenitor cells (NPCs) in a three-dimensional environment. Using single-cell RNA sequencing techniques, Monocle pseudotime trajectory and CellphoneDB analysis, we demonstrate that the stiffness of the hydrogel alone does not influence the differentiation of NPCs, but the degradation of the hydrogel that enhances cell-cell interactions is possibly the main reason. We also find that ECM remodeling facilitates cells to sense mechanical stimuli.

A Biostable l-DNA Hydrogel with Improved Stability for Biomedical Applications.

DNA hydrogels have attracted increasing attention owing to their excellent permeability and high mechanical strength, together with thixotropy, versatile programmability and good biocompatibility. However, the moderate biostability and immune stimulation of DNA have arisen as big concerns for future potential clinical applications. Herein, we report the self-assembly of a novel l-DNA hydrogel, which inherited the extraordinary physical properties of a d-DNA hydrogel. With the mirror-isomer deoxyribose, this hydrogel exhibited improved biostability, withstanding fetal bovine serum (FBS) for at least 1 month without evident decay of its mechanical properties. The low inflammatory response of the l-DNA hydrogel has been verified both in vitro and in vivo. Hence, this l-DNA hydrogel with outstanding biostability and biocompatibility can be anticipated to serve as an ideal 3D cell-culture matrix and implanted bio-scaffold for long-term biomedical applications.

Anti-Friction MSCs Delivery System Improves the Therapy for Severe Osteoarthritis.

Osteoarthritis (OA) is a musculoskeletal disorder disease affecting about 500 million people worldwide and mesenchymal sem cells (MSCs) therapy has been demonstrated as a potential strategy to treat OA. However, the shear forces during direct injection and the harsher shear condition of OA environments would lead to significant cell damage and inhibit the therapeutic efficacy. Herein, DNA supramolecular hydrogel has been applied as delivering material for MSCs to treat severe OA model, which perform extraordinary protection in MSCs against the shear force both in vitro and in vivo. It is demonstrated that the DNA supramolecular hydrogel can promote formation of quality cartilage, reduce osteophyte, and normalize subchondral bone under the high friction condition of OA, whose molecular mechanisms underlying therapeutic effects are also investigated. It can be anticipated that DNA supramolecular hydrogel would be a promising cell delivery system for multiple potential MSCs therapy.

Shear-Thinning and Designable Responsive Supramolecular DNA Hydrogels Based on Chemically Branched DNA.

A novel supramolecular DNA hydrogel system was designed based on a directly synthesized chemically branched DNA. For the hydrogel formation, a self-dimer DNA with two sticky ends was designed as the linker to induce the gelation of B-Y. By programing the linker sequence, thermal and metal-ion responsiveness could be introduced into this hydrogel system. This supramolecular DNA hydrogel shows shear-thinning, designable responsiveness, and good biocompatibility, which will simplify the hydrogel composition and preparation process of the supramolecular DNA hydrogel and accelerate its biomedical applications.

Highly Permeable DNA Supramolecular Hydrogel Promotes Neurogenesis and Functional Recovery after Completely Transected Spinal Cord Injury.

Regeneration after severe spinal cord injury cannot occur naturally in mammals. Transplanting stem cells to the injury site is a highly promising method, but it faces many challenges because it relies heavily on the microenvironment provided by both the lesion site and delivery material. Although mechanical properties, biocompatibility, and biodegradability of delivery materials have been extensively explored, their permeability has rarely been recognized. Here, a DNA hydrogel is designed with extremely high permeability to repair a 2 mm spinal cord gap in Sprague-Dawley rats. The rats recover basic hindlimb function with detectable motor-evoked potentials, and a renascent neural network is formed via the proliferation and differentiation of both implanted and endogenous stem cells. The signal at the lesion area is conveyed by, on average, 15 newly formed synapses. This hydrogel system offers great potential in clinical trials. Further, it should be easily adaptable to other tissue regeneration applications.

Recent Progress in DNA Motor-Based Functional Systems.

The designability, functionalization, and diverse secondary structures of DNA enable the construction of DNA motors with stimuli-responsiveness. Therefore, it has been widely used to fabricate functional systems or generate mechanical power under external stimuli, such as pH, light, heat, electrical, and chemical molecular signals. Furthermore, the DNA motor has also been demonstrated to promote the applications of smart devices and materials, particularly in controllable drug delivery and reversible molecular switching. In this review, we have summarized and discussed recent progress of the construction and applications of DNA motor-based functional systems, such as responsive nanodevices, modified surfaces, and hydrogels.

Constructing Tissuelike Complex Structures Using Cell-Laden DNA Hydrogel Bricks.

Tissue engineering has long been a challenge because of the difficulty of addressing the requirements that such an engineered tissue must meet. In this paper, we developed a new "brick-to-wall" based on unique properties of DNA supramolecular hydrogels to fabricate three-dimensional (3D) tissuelike structures: different cell types are encapsulated in DNA hydrogel bricks which are then combined to build 3D structures. Signal responsiveness of cells through the DNA gels was evaluated and it was discovered that the gel permits cell migration in 3D. The results demonstrated that this technology is convenient, effective and reliable for cell manipulation, and we believe that it will benefit artificial tissue fabrication and future large-scale production.