This study presents a novel approach for the early detection and monitoring of hepatocellular carcinoma (HCC) using exosomes enriched by a silicon dioxide (SiO₂) microsphere-coated 3D hierarchical porous chip. The SiO₂-chip, designed to enhance exosome capture efficiency, was validated for its ability to enrich exosomes from plasma samples. RNA sequencing of exosomes enriched by the SiO₂-chip identified two long non-coding RNAs (lncRNAs), LUCAT-1 and EGFR-AS-1, which are associated with HCC progression. These lncRNAs were further validated using quantitative real-time polymerase chain reaction (qRT-PCR). The combination of these lncRNAs with existing biomarkers such as alpha-fetoprotein (AFP) and des-γ-carboxy-prothrombin (DCP) significantly improved diagnostic accuracy and prognosis prediction in HCC patients. The study demonstrates the potential of this liquid biopsy-based approach for non-invasive HCC detection and monitoring, offering a promising tool for early diagnosis and management of HCC.This study presents a novel approach for the early detection and monitoring of hepatocellular carcinoma (HCC) using exosomes enriched by a silicon dioxide (SiO₂) microsphere-coated 3D hierarchical porous chip. The SiO₂-chip, designed to enhance exosome capture efficiency, was validated for its ability to enrich exosomes from plasma samples. RNA sequencing of exosomes enriched by the SiO₂-chip identified two long non-coding RNAs (lncRNAs), LUCAT-1 and EGFR-AS-1, which are associated with HCC progression. These lncRNAs were further validated using quantitative real-time polymerase chain reaction (qRT-PCR). The combination of these lncRNAs with existing biomarkers such as alpha-fetoprotein (AFP) and des-γ-carboxy-prothrombin (DCP) significantly improved diagnostic accuracy and prognosis prediction in HCC patients. The study demonstrates the potential of this liquid biopsy-based approach for non-invasive HCC detection and monitoring, offering a promising tool for early diagnosis and management of HCC.