Cell-free RNA fragmentomics: rethinking the biology of RNA liquid biopsies

Cell-free RNA (cfRNA) is emerging as a promising analyte for liquid biopsy because it captures dynamic changes in gene expression across tissues and disease states. However, interpretation of cfRNA profiles remains limited by the lack of a unifying framework describing how extracellular RNAs are released, processed, and stabilized. Here, we propose that concepts from cell-free DNA fragmentomics provide a useful lens to interpret cfRNA biology and introduce the concept of cfRNA fragmentomics. We argue that many cfRNAs originate as intracellular ribonucleoprotein complexes that undergo extracellular ribonuclease processing, generating stable fragmented RNAs associated with proteins and other carriers. Under this framework, informative cfRNA signatures may arise not only from diseased tissues but also from indirect systemic responses to disease.