Lymphatic endothelial cells (LECs) that form lymphatic vessels play a pivotal role in immune regulation. It was recently reported that LECs suppress the antigen-dependent anti-tumor immunity in cancer tissues. Thus, regulating the function of LECs is a promising strategy for cancer therapy. The objective of this study was to develop a method for the selective delivery of small interfering RNA (siRNA) to LECs. For this purpose, the siRNA was formulated into nanoparticles (LNPs) to prevent them from being degraded in body fluids and to facilitate their penetration of the cell membrane. A breakthrough technology for achieving this is ONPATTRO®, a world's first siRNA drug. Since LNPs are taken up by hepatocytes relatively well via low-density lipoprotein receptors, most of the LNP systems that have been developed so far target hepatocytes. In this study, we report on the development of a new method for the rapid and convenient method for modifying LNPs with antibodies using the CLick reaction on the Interface of the nanoParticle (CLIP). The CLIP approach was faster and more versatile than the conventional method using amide coupling. As a demonstration, we report on the LEC-targeted siRNA delivery by using antibody-modified LNPs both in vitro and in vivo. The method used for the modification of LNPs is highly promising and has the potential for expanding the LNP-based delivery of nucleic acids in the future.

形成淋巴管的淋巴管内皮细胞 (LEC) 在免疫调节中起关键作用。最近有报道称，LECs 可抑制癌组织中抗原依赖性抗肿瘤免疫。因此，调节 LEC 的功能是一种很有前景的癌症治疗策略。本研究的目的是开发一种将小干扰 RNA (siRNA) 选择性递送至 LEC 的方法。为此，将 siRNA 配制成纳米颗粒 (LNP) 以防止它们在体液中降解并促进它们穿透细胞膜。实现这一目标的突破性技术是世界上第一个 siRNA 药物 ONPATTRO®。由于 LNP 被肝细胞通过低密度脂蛋白受体，迄今为止开发的大多数 LNP 系统都针对肝细胞。在这项研究中，我们报告了一种使用纳米粒子界面上的 CLick 反应 (CLIP) 快速方便地用抗体修饰 LNP 的新方法的开发。CLIP 方法比使用酰胺偶联的传统方法更快、更通用。作为演示，我们报告了通过在体外和体内使用抗体修饰的 LNP 进行 LEC 靶向 siRNA 递送。用于修饰 LNP 的方法非常有前景，并有可能在未来扩展基于 LNP 的核酸递送。