of extracellular DNA in tissues and in circulation. [5] Extracellular DNA is capable of engaging with the immune system as depicted in Figure 1; therefore, as synthetic DNA-based biomaterials emerge, their potential immune responses must be considered. DNA sensors are mediators of extracellular DNA immune responses observed in vivo, including cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and toll-like receptors (TLRs). Defining novel DNA sensors and their mechanisms is an active area of investigation. [6] Likewise, the structural and chemical properties of DNA that triggers DNA sensors continue to be uncovered. [6] This review summarizes known DNA interaction modalities with the immune system, the sources of extracellular DNA, and, finally, the relevant and emerging biotechnologies that incorporate DNA molecules. A focus is geared toward innate immune responses and doublestranded DNA (dsDNA). Leveraging the immunomodulatory capacity of DNA enables tailoring materials to initiate specific immune outcomes depending on the application, for instance, priming aggressive immune responses for localized tumor-interfacing biomaterials or immunosuppressive functions to prevent chronic inflammation on implant surfaces. Achieving this requires an improved understanding of the DNA properties, such as backbone chemistry, base pair sequence, charge, and length, that can function as design levers for the immune response.
The Role of Extracellular DNA in the Immune ResponseThe immune system is designed to protect the host against infections by distinguishing between self-and non-self motifs, and by identifying pathogen and damage signals. Upon recognition of a "non-self" or foreign molecule, an array of effector functions are triggered and orchestrated by immune cells to achieve pathogen clearance and restore homeostasis. [7] These immunoactivating defense mechanisms include the release of proinflammatory cytokines, immune cell recruitment, programmed cell death, and phagocytosis. Ideally, immunoactivating responses are supplanted by immunosuppressive functions once the pathogen or agonist is resolved. This immune resolution is necessary to coordinate healing and anti-inflammatory functions such as diminished chemokine and cytokine secretion, replacement Man-made DNA materials hold the potential to modulate specific immune pathways toward immunoactivating or immunosuppressive cascades. DNAbased 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 mole...