文献：Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors

文献链接：https://xueshu.baidu.com/usercenter/paper/show?paperid=1a7e0ea0qj0g06g03v2m0mn0dt692410&site=xueshu_se

作者：Yukun Huang, Yu Chen , Songlei Zhou, Liang Chen, Jiahao Wang, Yuanyuan Pei, Minjun Xu, Jingxian Feng, Tianze Jiang, Kaifan Liang, Shanshan Liu, Qingxiang Song, Gan Jiang , Xiao Gu, Qian Zhang, Xiaoling Gao & Jun Chen

相关产品：DSPE-PEG2000 磷脂-聚乙二醇2000

原文摘要：The failure of immunotherapies in immune-excluded tumor (IET) is largely ascribed to the void of intratumoral cytotoxic T cells (CTLs). The major obstacles are the excessive stroma,defective vasculatures and the deficiency of signals recruiting CTLs. Here we report a dualmechanism based CTLs infiltration enhancer, Nano-sapper, which can simultaneously reduce the physical obstacles in tumor microenvironment and recruiting CTLs to potentiate immunotherapy in IET. Nano-sapper consists a core that co-loaded with antifibrotic phosphates modified α-mangostin and plasmid encoding immune-enhanced cytokine LIGHT. Through reversing the abnormal activated fibroblasts, decreasing collagen deposition, normalizing the intratumoral vasculatures, and in situ stimulating the lymphocyte-recruiting chemoattractants expression, Nano-sapper paves the road for the CTLs infiltration, induces the intratumoral tertiary lymphoid structures, thus reshapes tumor microenvironment and potentiates checkpoint inhibitor against IET. This study demonstrates that the combination of antifibrotic agent and immune-enhanced cytokine might represent a modality in promoting immunotherapy against IET.

磷脂-聚乙二醇 2000（Phospholipid-PEG2000）是一种生物材料复合物。磷脂疏水的脂肪酸链与亲水的头部基团，使其能够在水性环境中自发形成脂质双层结构，这为构建脂质体、胶束等纳米载体提供了基础框架，可有效包裹化合物、基因等生物活性物质。聚乙二醇有助于在生物体内的分散与运输；同时，它能有效减少蛋白质和细胞对材料的非特异性吸附，延长在体内的循环半衰期，使所载物质能够更持久地发挥作用。该产品可提高化合物的稳定性、生物利用度和靶向性。 基于此，该文献报道了一种基于双机制的ctl浸润增强剂，纳米传感器。它可以同时减少tumor微环境中的物理障碍，并引入ctl来增强IET的效果。过程如下：

图：纳米工材与免疫检查点抑制剂的预期协同作用

纳米工材的制备

纳米器的制备如图所示。简单地说，通过反相微乳液合成质粒CaMP核，然后在减压下与胆固醇、DOTAP、DSPE-PEG2000和DSPE-PEG2000-FHK形成薄膜。然后，用的蔗糖溶液水合脂质膜，获得纳米边材。内核通过钙离子与MP/质粒的相互作用沉淀，随后被外部带有FHK肽的不对称脂质双分子层覆盖。通过FHK-CaMP（不含pLIGHT）和FHK-pLIGHT@CaP（不含MP）制备相同的过程，除了核心组件的变化。对于pLIGHT，将光的胞外结构域和c端三聚体结构域的编码序列合并起来组装光质粒。

图：采用反相微乳液和薄膜水化法制备了纳米材料

结论：DSPE-PEG2000参与制备的纳米供材由一个核心与抗纤维化磷酸化α-锰素和编码免疫增强细胞因子光的质粒共同组成。通过逆转异常激活的成纤维细胞，减少胶原沉积，并原位刺激Lymph 细胞吸引趋化剂的表达，纳米传感器为ctl的浸润铺平了道路，从而重塑tumor微环境，增强针对IET的检查点抑制剂。