Background: Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide. Although colonoscopy and stool-based screening tests have improved early detection, participation, invasiveness, and limited sensitivity for some precancerous lesions remain important challenges. Liquid biopsy offers a minimally invasive approach for detecting tumor-derived molecular signals in blood, particularly circulating tumor DNA (ctDNA) and Exosomal biomarkers.

Objective: This review evaluates the biological rationale, diagnostic performance, clinical applications, and limitations of ctDNA and exosome-derived biomarkers for early CRC detection.

Methods: A narrative evidence synthesis developed from peer-reviewed clinical studies, diagnostic accuracy investigations, systematic reviews, and meta-analyses. Evidence organized according to biomarker type, molecular detection method, clinical population, diagnostic accuracy, and translational readiness. Published diagnostic estimates distinguished from interpretive conclusions; no new-pooled estimate calculated from individual studies.

Results: ctDNA assays detect tumor-associated mutations, methylation patterns, and frag entomic characteristics, whereas Exosomal biomarkers include microRNAs, proteins, and other molecular cargo protected within extracellular vesicles. In the prospective ECLIPSE study, a cell-free DNA blood test demonstrated 83.1% sensitivity for CRC and 89.6% specificity for advanced colorectal neoplasia, but sensitivity for advanced precancerous lesions was only 13.2% (Chung et al., 2024). Exosomal microRNA studies have identified promising candidate panels, although differences in isolation procedures, normalization, and study populations limit cross-study comparability. Combining complementary molecular signals may improve detection, but prospective population-based validation remains essential.

Conclusion: Liquid biopsy has substantial potential as a complementary CRC screening strategy. Its clinical value will depend on reproducible analytical methods, high sensitivity for early-stage disease and advanced precancerous lesions, appropriate specificity in asymptomatic populations, cost-effectiveness, and demonstrated benefits in screening participation and patient outcomes.