Reprogramming the gut-liver immune axis: probiotic-derived extracellular vesicles as precision nanotherapeutics in hepatocellular carcinoma.

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide and exhibits limited responsiveness to immune checkpoint inhibitors (ICIs), largely due to profound tumor-associated immunosuppression and the complexity of gut–liver immune crosstalk. Probiotic-derived extracellular vesicles (PEVs) have recently emerged as biologically active mediators capable of delivering immunomodulatory cargos and influencing host immune pathways. This mini-narrative review critically evaluates the evolving role of PEVs in liver disease and their emerging relevance to HCC. OBJECTIVE: This review examines the molecular composition, immunomodulatory mechanisms, and translational potential of PEVs in the context of HCC, with an emphasis on delineating direct evidence from pre-malignant and supportive disease models. METHODS: We synthesized evidence from recent preclinical and translational studies (2020–2026) addressing PEV biogenesis, cargo–target interactions, immune modulation within hepatic microenvironments, and emerging delivery and manufacturing strategies. RESULTS: Accumulating preclinical evidence demonstrates that PEVs can modulate innate and adaptive immune pathways most robustly in inflammatory and pre-malignant liver disease models by promoting dendritic cell maturation, enhancing cytotoxic T-cell responses, and attenuating immunosuppressive myeloid and regulatory T-cell programs. Advances in vesicle purification, nanoformulation, and targeting strategies have improved PEV stability and biodistribution, supporting their evaluation as complementary modalities alongside existing therapies. However, direct validation of these effects in established HCC models remains limited, warranting cautious interpretation. CONCLUSION: PEVs represent a versatile and biocompatible platform with emerging relevance to immune modulation in liver disease and HCC. While current evidence supports their immunoregulatory potential primarily in pre-malignant settings, successful clinical translation will require rigorous liver-relevant validation, standardized manufacturing and dosing frameworks, and carefully designed early-phase clinical studies. FUTURE PERSPECTIVES: Key priorities include elucidating in vivo biodistribution, refining cargo–target specificity, establishing potency assays, and integrating PEV-based strategies into rational combination regimens to define their therapeutic boundaries in HCC. CLINICAL TRIAL NUMBER: Not applicable.