Primary bile acids were reported to augment secretion of chemokine (C‒X‒C motif) ligand 16 (CXCL16) from liver sinusoidal endothelial cells (LSECs) and trigger natural killer T (NKT) cell-based immunotherapy for liver cancer. However, abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control. Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation, we proposed a strategy using nanoemulsion-loaded obeticholic acid (OCA), a clinically approved selective farnesoid X receptor (FXR) agonist, for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy. The OCA-nanoemulsion (OCA-NE) was prepared via ultrasonic emulsification method, with a diameter of 184 nm and good stability. In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells. As a result, OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model, which performed much better than oral medication of free OCA. Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-γ, as well as increased NKT cell populations inside the tumor. Overall, our research provides a new evidence for the antitumor effect of receptors for primary bile acids, and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy

据报道，初级胆汁酸可增强肝窦内皮细胞 (LSEC) 趋化因子（C-X-C 基序）配体 16 (CXCL16) 的分泌，并引发基于自然杀伤 T (NKT) 细胞的肝癌免疫治疗。然而，初级胆汁酸受体在胃肠道中的大量表达压倒了使用针对这些受体的激动剂来控制肝癌的可能性。利用 LSEC 捕获循环中循环纳米颗粒的固有特性，我们提出了一种策略，使用纳米乳液负载的奥贝胆酸 (OCA)（一种临床批准的选择性法尼醇 X 受体 (FXR) 激动剂）来精确操纵 LSEC 来触发 NKT 细胞介导的肝癌免疫治疗。采用超声乳化法制备OCA纳米乳液（OCA-NE），粒径为184 nm，稳定性良好。体内生物分布研究证实，注射的 OCA-NE 主要在肝脏中积累，尤其是在 LSEC 和 Kupffer 细胞中。结果，OCA-NE 治疗显着抑制了小鼠原位 H22 肿瘤模型中的肝肿瘤生长，其效果比游离 OCA 的口服药物好得多。免疫学分析显示，OCA-NE 导致 CXCL16 和 IFN- γ的分泌增加，以及肿瘤内 NKT 细胞群的增加。总体而言，我们的研究为初级胆汁酸受体的抗肿瘤作用提供了新的证据，并应启发使用纳米技术精确操纵 LSEC 进行肝癌治疗