How Extracellular DNA Structure Shapes Infection, Immunity, and Inflammation

Extracellular DNA—DNA released outside of cells—is a common feature of conditions seen across emergency medicine. In chronic wounds and device-associated infections, it stabilizes bacterial biofilms, forming part of the adhesive matrix that makes these infections persistent and difficult to eradicate.

In acute infections and systemic inflammation, neutrophils release DNA into the extracellular space, forming neutrophil extracellular traps, or NETs. These DNA-based structures trap and help kill pathogens during sepsis, pneumonia, and other infectious conditions.

 Excessive NET formation can lead to chronic inflammation, tissue damage, and blood vessel blockage from thrombosis. Recent studies also suggest that NETs play roles in many diseases beyond infection, including autoimmune diseases, cancer, neurodegenerative diseases, and metabolic disorders.

But what if extracellular DNA is not simply structural material? What if its shape determines whether it protects the host—or contributes to disease?

In a new perspective published in Nucleic Acids Research, Samuel Yang, MD, and colleagues explore how different DNA shapes influence interactions between microbes and the immune system in biofilms and NETs.

“Inside cells, alternative DNA shapes help regulate gene activity and maintain genomic stability. Outside the cell, their roles are only beginning to be understood,” says Dr. Yang, professor of emergency medicine at Stanford. “These structures are not incidental—they may actively shape how extracellular DNA functions in both biofilms and immune responses.”

A Molecular Double-Edged Sword

One hypothesis is that the same DNA structure can have opposing effects depending on context.

In NETs, a folded form of DNA known as G4 can bind to hemin and act like a small enzyme. Together, they generate reactive oxygen molecules that contribute directly to bacterial killing. In this setting, these unusual DNA shapes enhance innate immune defense.

In biofilms, however, the story shifts. G4 bound to hemin helps bacteria manage oxidative stress and generate energy in low-oxygen conditions, making the biofilm more resilient. That can:

• Protect bacteria from immune attack
• Increase resistance to antibiotics
• Prolonged infection

So while the same DNA structure helps kill bacteria in NETs, in biofilms it can strengthen bacterial survival.

“In other words,” says Dr. Yang, “The same DNA structure that enhances immune killing in one setting can promote bacterial survival in another. This suggests a kind of evolutionary arms race, with both host and microbe leveraging similar DNA architectures to gain an advantage.”

Implications for Autoimmunity and Inflammation

The identification of Z-DNA outside cells may also have implications for autoimmune disease. Z-DNA is a less common, left-handed form of the DNA double helix that can form under conditions of stress or inflammation. Antibodies against Z-DNA are found in patients with systemic lupus erythematosus—and, notably, in some healthy individuals as well.

The authors suggest that Z-DNA released during NET formation could act as a trigger for the immune system. In this model, the body may mistake this altered form of its own DNA for something foreign. This challenges traditional ideas about how immune tolerance is maintained and how autoantibodies develop.

Unusual DNA shapes may also affect how the immune system detects extracellular DNA. Because G4 and Z-DNA are harder to break down, they may stay in tissues longer. That persistence could keep the immune system activated and contribute to ongoing inflammation, clotting problems, and organ damage.

For emergency clinicians, this raises important questions. Could the structural state of extracellular DNA influence outcomes in sepsis, ARDS, or COVID-associated thrombosis? If NETs are not cleared efficiently—particularly when their DNA is structurally resistant—could that amplify systemic inflammation?

Therapeutic Opportunity Without Immune Suppression

Rather than broadly suppressing NET formation, the authors suggest a more targeted strategy: modifying these unusual DNA structures so they can be cleared more easily, while still allowing them to fight infection.

In biofilms, breaking down G4 or Z-DNA could weaken the biofilm structure and make it easier for enzymes and antibiotics to work. Possible strategies include drugs like chloroquine, antibodies that target DNABII proteins, or molecules designed to disrupt G4 structures.

In diseases involving NETs, helping the body clear hard-to-break-down DNA may be a better approach than stopping NET formation altogether.

Reframing Extracellular DNA

This work reframes extracellular DNA as an active participant in disease biology, not simply residual material. Extracellular DNA like G4 and Z-DNA can be protective during acute infection, yet potentially pathogenic when persistent or dysregulated.

For academic emergency medicine, the implications span chronic biofilm-associated infection, autoimmune disease, thromboinflammation, and critical illness. Understanding how the shape of DNA affects interactions between the immune system and microbes may open a new layer of therapeutic targeting in conditions frequently encountered in the emergency department.

Research has largely focused on how much extracellular DNA is present or the proteins associated with the DNA. This study suggests that how it is structured may be equally important.

News updated March 2026