How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Using progeroid mice carrying an ERCC1-XPF DNA repair defect, we find that persistent DNA damage leads to cellular senescence, fibrosis, loss of tissue architecture and chronic pancreatitis in Ercc1-/- mice. We show that DNA damage-driven R-loops causally contribute to the active release and build-up of single-stranded (ss)DNAs in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or RNase H nucleases in inflamed Ercc1-/- pancreatic cells. Importantly, treatment of Ercc1-/- animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration with advancing age paving the way for novel rationalized intervention strategies against age-related chronic inflammation.
