Lipid nanoparticles and extracellular vesicles: emerging cell free therapeutic platforms for hepatobiliary cancers

Hepatobiliary cancers are major contributors to cancer-related mortality, mainly due to late-stage diagnosis, poor prognosis, and limited effectiveness of current treatments in advanced disease. Standard therapies comprise surgical resection, liver transplantation, and systemic agents including tyrosine kinase inhibitors and immune checkpoint inhibitors, but their efficacy is often hindered by the development of drug resistance, underlying the urgent need for novel therapeutic strategies. Lipid nanoparticles (LNPs) have emerged as promising delivery vehicles due to their favorable physicochemical properties, enabling the transport of natural biomolecules or engineered drugs for targeted tumor therapy. LNPs are also being explored as platforms for cancer therapy and vaccines. Moreover, recent advances underscore the key role of extracellular vesicles (EVs) in modulating the tumor microenvironment, promoting tumor progression, chemoresistance, and escape from immune recognition and destruction (immune evasion) in hepatobiliary cancers. EVs are being investigated both as biomarkers for early detection and as therapeutic agents, with engineered or drug-loaded EVs showing potential for targeted drug delivery and tissue repair in liver diseases, including cancer. This review highlights the potential of cell-free therapeutic LNP- and EV-based platforms, standalone or in combination, for RNA, small molecules and proteins delivery in improving diagnosis and treatment outcomes in hepatobiliary cancers, in particular, hepatocellular carcinoma and cholangiocarcinoma.