Promising novel biomarkers and therapy targets: The application of cell-free seminal nucleotides in male reproduction research

Liquid biopsy has the advantage of diagnosing diseases in a non-invasive manner. Seminal plasma contains secretions from the bilateral testes, epididymides, seminal vesicles, bulbourethral glands, and the prostate. These organs are relatively small and contain delicate tubes that are prone to damage by invasive diagnosis. Cell-free seminal nucleic acids are a newly emerged item in liquid biopsy. Here, we present a comprehensive overview of all known cell-free DNA and cell-free RNAs (mRNA, miRNA, lncRNA, circRNA, piRNA, YRNA, tsRNA, etc.) and discuss their roles as biomarker candidates in liquid biopsy. With great advantages, including high stability, sensitivity, representability, and non-invasiveness, cell-free DNA/RNAs may be developed as promising biomarkers for the screening, diagnosis, prognosis, and follow-up of diseases in semen-secreting organs. Moreover, RNAs in semen may participate in important processes, including sperm maturation, early embryo development, and transgenerational disease inheritance, which may be developed as potential treatment targets for future clinical use.