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To address this, we developed NEXPLOR (Novel EXtracellular vesicle PopuLation Omics Revealer), an immunoaffinity platform enabling selective enrichment of circulating tissue\u2010specific extracellular vesicles (TS\u2010EVs), demonstrated here for liver\u2010derived hepatocyte\u2010EVs (h\u2010EVs). Through in silico discovery and orthogonal antibody validation across tissues, we identified a four\u2010marker panel (ASGR1, ASGR2, TFR2, SLCO1B1) that selectively enriched hepatocyte EVs without co\u2010capturing the dominant platelet\u2010 and leukocyte\u2010EV background. In a clinical cohort of hepatocellular carcinoma (HCC), non\u2010cancer cirrhosis and healthy donors, NEXPLOR recovered 57% more proteins than bulk EV isolation, with greater reproducibility. By restoring tissue context, h\u2010EVs exposed liver biology that bulk EVs miss, spanning three levels: metabolic pathways (carbon metabolism, HIF\u20101\u03b1 signalling, ferroptosis), HCC\u2010defining proteins (PGD, H2AZ1, PRDX5), and progression\u2010tracking candidates (CFB, PCSK9). Small RNA sequencing detected five miRNAs upregulated in HCC versus cirrhosis h\u2010EVs, against 21 in bulk EVs (no overlap); yet only the h\u2010EV miRNAs mapped to HCC\u2010relevant signalling, and hepatocyte\u2010regulatory miR\u2010124\u20103p appeared exclusively in h\u2010EVs. Together, these results establish tissue\u2010specific EV enrichment as a route to more actionable, multi\u2010omic liquid biopsies in HCC, cirrhosis and other diseases in urgent need of non\u2010invasive biomarkers for patient diagnosis, monitoring and stratification.<\/jats:p>","DOI":"10.1002\/jev2.70372","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T17:13:45Z","timestamp":1791652425000},"source":"Crossref","is-referenced-by-count":0,"title":["Tissue\u2010Specific Isolation of Hepatocyte Extracellular Vesicles From Human Plasma Enables Tissue\u2010Resolved Proteomic and miRNA Profiling"],"prefix":"10.1002","volume":"15","author":[{"given":"Ricardo","family":"Figueiras","sequence":"first","affiliation":[{"name":"Mursla Bio  Cambridge UK"},{"name":"Mursla Bio  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Vagueiro","sequence":"additional","affiliation":[{"name":"Mursla Bio  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