A promising frontier of circulating messenger RNA in liquid biopsy: From mechanisms to clinical applications

Abstract

Liquid biopsy can revolutionize cancer patient management as repeated sampling allows real-time monitoring of disease progression and response to treatment. The circulating transcriptome represents a rich source of potential cancer biomarkers, including coding and non-coding RNAs. As techniques that have enabled us to analyze transcriptome profiling become ever more sophisticated, the great potential of extracellular messenger RNA (mRNA) and intracellular (cellular level) mRNA in liquid biopsy has gradually been realized. In this review, we aim to conclude the mRNA-based liquid biopsy in the tumorous context by illustrating the origins of mRNA markers and scientific findings, and summarizing the advantages of mRNAs over DNA-based liquid biopsy. Besides, we give a glimpse of the application of this strategy in clinical studies and analyze the gap between the bench and bedside. We speculate that mRNAs are a promising frontier of liquid biopsy.

Keywords: cell‐free RNA; circulating tumor cell; extracellular vesicle; liquid biopsy; messenger RNA.

FIGURE 1

Analytes for liquid biopsy‐based approaches and types of RNA in liquid biopsy. (A) Liquid biopsy primarily serves as a blood‐based diagnostic tool that analyzes circulating tumor cells, tumor‐derived biomolecules (including circulating tumor DNA, various types of RNA, and metabolites), extracellular vesicles, and tumor‐educated platelets. (B) Tumor‐derived RNAs examined in liquid biopsy mainly consist of messenger RNA (mRNA), microRNA (miRNA), circular RNA (circRNA), long non‐coding RNA (lncRNA), among others.

FIGURE 2

Biosources of mRNA and their potential roles in liquid biopsy. (A) Various biofluids, including peripheral blood, blood‐derived components (e.g., plasma, serum), and urine, harbor detectable messenger RNA (mRNA) molecules. (B) In liquid biopsy, mRNA is primarily derived from circulating tumor cells (CTC), extracellular vesicles (EV), tumor‐educated platelets (TEP), and protein‐bound mRNA complexes, such as ribonucleoproteins (RNP). (C) Whole blood and whole urine represent the most extensively studied whole biofluids for mRNA‐based biomarker detection due to their non‐invasive accessibility and rich molecular content. (D) Circulating mRNA profiles offer valuable clinical insights, including identification of response biomarkers and tumor‐associated genomic alterations, prognostic and predictive signatures for therapy response, and elucidation of tumor biology mechanisms. Integrating mRNA analysis with conventional clinical risk factors and other liquid biopsy modalities—such as circulating tumor DNA (ctDNA) and non‐coding RNA (ncRNA)—may enhance diagnostic and monitoring accuracy.