eDNA: A dual nongenetic gamechanger in biofilm development and depletion.

Biofilms, first described by Anthony van Leeuwenhoek (1632-1723), are surface-attached, organized microbial communities. They form when single cells embed within an extracellular matrix (ECM) composed mainly of extracellular polymeric substances (EPS), enabling a multicellular lifestyle. Extracellular DNA (eDNA), a major EPS component, makes up a substantial portion of biofilm biomass. It interacts with polysaccharides, proteins, and nucleic acids to create a stable network that reinforces biofilm structure. eDNA, present in all biofilm ECM, plays a paradoxical role in bacterial survival. It is vital for structural integrity, guiding the biofilm from initial attachment through maturation and dispersion, yet this dependence also creates a critical vulnerability. Recent research highlights that while eDNA supports biofilm growth, disrupting its release, interactions, or structure destabilizes the matrix and drives depletion. Recognizing eDNA as both a structural scaffold and a therapeutic target enables more effective strategies to inhibit and disperse resilient biofilm communities. This review highlights recent advances in eDNA-releasing mechanisms, its multifunctional roles in biofilm support, and how its structures and interactions regulate development. We further show that modulating eDNA provides a targeted strategy for antibiofilm therapy and clinical dispersal. Notably, eDNA itself may also act as a cue for biofilm inhibition.