The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment
The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment
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LY3200882 和 PD-L1 siRNA 的程序化位点特异性递送通过重塑肿瘤微环境增强三阴性乳腺癌的免疫治疗
DOI：
10.1016/j.biomaterials.2022.121518
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发表时间：
2022
期刊：
影响因子：
14
通讯作者：
Meirong Huo
中科院分区：
文献类型：
--
作者：
Pan Zhang;Chao Qin;Nan Liu;Xinyuan Zhou;Xuxin Chu;Fangnan Lv;Yongwei Gu;Lifang Yin;Jiyong Liu;Jianping Zhou;Meirong Huo
尽管免疫疗法在过去十年中取得了显着的成功，但其对三阴性乳腺癌（TNBC）的有效性仅限于一小部分患者，主要是由于低免疫原性和不利的肿瘤微环境。在这项研究中，我们成功地构建了一个程序化的位点特异性递送纳米系统，用于联合递送转化生长因子β（TGF-β）受体抑制剂LY 3200882（LY）和PD-L1 siRNA（siPD-L1），以增强抗肿瘤免疫治疗。正如预期的那样，纳米系统外层的LY通过刺激MMP 2而释放，并显著下调肿瘤相关成纤维细胞（TAFs）中细胞外基质（ECM）的表达，从而促进效应T细胞的浸润和纳米药物的渗透。同时，LY对TGF-β的阻断还引发肿瘤细胞的免疫原性细胞死亡（ICD）并诱导树突状细胞的成熟。此外，程序化设计使siPD-L1/鱼精蛋白阳离子内核在MMP 2刺激的外层破裂后更容易接近肿瘤细胞和TAF，从而下调两种类型细胞中PD-L1的表达。值得注意的是，LY和siPD-L1的协同作用显著增强了肿瘤抗原呈递和免疫抑制微环境重塑，从而有效地抑制了TNBC的生长、转移和复发。因此，程序化的位点特异性递送纳米系统是用于增强TNBC的抗肿瘤免疫治疗功效的有前景的药物递送平台。
Despite the remarkable success of immunotherapies over the past decade, their effectiveness against triple-negative breast cancer (TNBC) is limited to a small subset of patients, mainly due to the low immunogenicity and unfavorable tumor microenvironment. In this study, we successfully constructed a programmed site-specific delivery nanosystem for the combined delivery of transforming growth factor beta (TGF-β) receptor inhibitor LY3200882 (LY) and PD-L1 siRNA (siPD-L1) to boost anti-tumor immunotherapy. As expected, LY in the outer layer of the nanosystem was released by stimulation of MMP2, and dramatically down-regulated the expression of extracellular matrix (ECM) in the tumor-associated fibroblasts (TAFs), and thus promoted the infiltration of effector T cells and penetration of nanomedicines. Simultaneously, the blockade of TGF-β by LY also triggered immunogenic cell death (ICD) of tumor cells and induced the maturation of dendritic cells. Moreover, the programmed design provided the siPD-L1/protamine cationic inner core with easier access to tumor cells and TAFs after MMP2-stimulated breakup of the outer layer, down-regulating the expression of PD-L1 in both types of cells. Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC.