DNA-Based Biomaterials for Immunoengineering

Abstract

Man-made DNA materials hold the potential to modulate specific immune pathways toward immunoactivating or immunosuppressive cascades. DNA-based biomaterials introduce DNA into the extracellular environment during implantation or delivery, and subsequently intracellularly upon phagocytosis or degradation of the material. Therefore, the immunogenic functionality of biological and synthetic extracellular DNA should be considered to achieve desired immune responses. In vivo, extracellular DNA from both endogenous and exogenous sources holds immunoactivating functions which can be traced back to the molecular features of DNA, such as sequence and length. Extracellular DNA is recognized as damage-associated molecular patterns (DAMPs), or pathogen-associated molecular patterns (PAMPs), by immune cell receptors, activating either proinflammatory signaling pathways or immunosuppressive cell functions. Although extracellular DNA promotes protective immune responses during early inflammation such as bacterial killing, recent advances demonstrate that unresolved and elevated DNA concentrations may contribute to the pathogenesis of autoimmune diseases, cancer, and fibrosis. Therefore, addressing the immunogenicity of DNA enables immune responses to be engineered by optimizing their activating and suppressive performance per application. To this end, emerging biology relevant to the generation of extracellular DNA, DNA sensors, and its role concerning existing and future synthetic DNA biomaterials are reviewed.

Keywords: DNA; NETs; biomaterials; eDNA; immunoregulation.

Figure 1.. The role of DNA in the immune system.

Beyond its role as an information-encoding molecule (left), DNA has immune functions when introduced into the extracellular milieu. DNA engages with immune cells to initiate either immunoactivating and immunosuppressive responses. Depicted on the right is extracellular DNA activating the DNA sensor, TLR-9, upon internalization by phagocytosis. TLR activates NF-kB signaling leading to the release of pro-inflammatory cytokines, amplifying the immune response. Created with BioRender.

Figure 2.. Types of cell death and resulting DNA release.

The top row depicts types of cell death and morphology and the bottom row illustrates DNA size and morphology upon cell death. The columns from left to right correspond to apoptosis, necrosis, and ETosis, respectively. Created with BioRender.

Figure 3.. The Production-Degradation Balance of Extracellular DNA.

The immune system requires a balance between extracellular DNA production and degradation. The mechanisms of release and their pathological implications are outlined. Over-production may lead to cell death by-products, defective nucleases, and cellular stress. ^[5][44][53] These have been found to have implications in lupus, cancer, and arthritis. ^[45]–[47] On the other hand, insufficient extracellular DNA by phagocytosis or enzymatic clearance, such as DNAse 1, can lead to host susceptibility of infections. ^{[6][23][43][44]} Created with BioRender.

Figure 4.. Engineered DNA biomaterials.

Emerging DNA-based biomaterials were classified broadly into categories: ODN, chemically-modified DNA, DNA hybridization, DNA-nanoparticle conjugates, and DNA-protein complexes.