Unravelling the noncanonical extracellular DNA structures in biofilm and NETosis

Noncanonical secondary structures of DNA have been well characterized in vitro for their catalytic and sensory functions, as well as in vivo for their regulatory functions in the genome. However, their presence and functional significance in the extracellular DNA (eDNA), particularly within biofilms and neutrophil extracellular traps (NETs), have only recently begun to be appreciated and have yet to be fully understood. Emerging studies have identified these atypical DNA conformations as integral components that contribute to the structural stability of biofilms and antimicrobial activity of NETs. In this personal view, we advocate for a comprehensive investigation of these unconventional DNA structures within extracellular contexts, where their distinct physiochemical properties are exposed to dynamic and unpredictable microenvironments, with the potential to profoundly influence microbial behaviour, immune responses, and host-pathogen interactions. Considering the broad spectrum of diseases associated with biofilm and NETs, targeting noncanonical eDNA structures may offer novel therapeutic avenues and shed light on mechanisms of immune tolerance and dysregulation.