Nanoparticle-based delivery system for normalization of liver sinusoidal endothelial cells in hepatocellular carcinoma

• Abnormal vasculature can promote immunosuppressive tumor microenvironment in HCC. • Normalization of capillarized LSECs improves the efficacy of immune checkpoint blockade in HCC. • Targeting abnormal LSEC destruction and normalization by nanoparticle-delivery system demonstrates a promising strategy to enhance immunotherapy efficacy in HCC. Liver sinusoidal endothelial cells (LSECs) are the predominant endothelial cells (ECs) and the most abundant type of non-parenchymal cells (NPCs) in the liver, lining the low-shear sinusoidal channels. LSECs are not only a physical barrier but play multifunctional roles, like endocytosis, antigen presentation, and immune cell trafficking, as well as positively promoting disease development patho-physiologically. In physical conditions, LSEC demonstrates unique structures that can distinguish it from other endothelia in other organs. Capillarization of LSEC, a dysfunctional phenotype, is the essential event from fibrosis to cirrhosis and finally to hepatocellular carcinoma (HCC). They further precede angiogenesis and vasoconstriction, facilitating the immunosuppressive microenvironment. Targeting abnormal ECs in HCC has demonstrated great potential in enhancing the efficacy of immunotherapy. Multiple approaches have been employed for EC normalization, including nanoparticles (NPs). Evidence has shown that NP-mediated drug systems can greatly normalize ECs and increase anti-tumor efficiency. This review discusses multiple NP platforms, focusing on their potential in HCC. We further discuss the immune modulation of tumor microenvironment (TME) through NP application in HCC.