Systematic Review of Extracellular Vesicle-Based Liquid Biopsy for Leptomeningeal Metastasis: Current Evidence and Future Directions

Leptomeningeal Metastasis (LM) is a catastrophic complication of systemic malignancies with poor prognosis and significant diagnostic challenges. Extracellular vesicle (EV)-based liquid biopsy is an emerging technology that may improve the detection, prognosis, and therapeutic monitoring for LM. This systematic review aims to critically appraise and synthesize existing evidence on the use of EV-derived biomarkers from cerebrospinal fluid (CSF) or serum for the diagnosis, prognosis, and therapeutic monitoring of LM. A systematic search of PubMed, ScienceDirect, Semantic Scholar, and Google Scholar was conducted up to January 2025. Eligible studies evaluated EV-associated molecular biomarkers (microRNAs or proteins) in LM patients using CSF or serum samples. Data extraction included study design, sample source, EV isolation method, biomarker type, validation method, and diagnostic/prognostic relevance. Risk of bias was assessed using QUADAS-2. Ten studies met inclusion criteria, encompassing EV miRNA and proteomic profiling in LM, primarily from non-small cell lung cancer (NSCLC) and medulloblastoma. miR-21 consistently correlated with poor prognosis and therapy resistance. Novel candidates such as miR-183-5p demonstrated high diagnostic accuracy (AUC 1.0 in a discovery cohort), targeting PTEN pathways. EV-derived proteins including fibronectin-1 (FN1), transketolase (TKT), and complement C2 also showed strong discriminative potential. Heterogeneity in EV isolation techniques and small sample sizes limited meta-analysis feasibility. EV-based liquid biopsy holds cautious promise as a minimally invasive tool for LM diagnosis, prognosis, and therapeutic monitoring. Larger, multicenter studies with standardized protocols are required to validate these findings and facilitate clinical translation.