Size/Charge Changeable Acidity-Responsive Micelleplex for Photodynamic-Improved PD-L1 Immunotherapy with Enhanced Tumor Penetration
Size/Charge Changeable Acidity-Responsive Micelleplex for Photodynamic-Improved PD-L1 Immunotherapy with Enhanced Tumor Penetration
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DOI：
10.1002/adfm.201707249
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发表时间：
2018-05-04
影响因子：
19
通讯作者：
Cai, Kaiyong
中科院分区：
文献类型：
--
作者：
Dai, Liangliang;Li, Ke;Cai, Kaiyong
基于检查点阻断的免疫疗法最近已成为一种有前途的肿瘤治疗方法，但其临床实施受到纳米载体的肿瘤渗透性差和抗肿瘤免疫应答激活的阻碍。为了克服这些障碍，本研究报道了一种与程序性死亡配体1（PD-L1）阻断siRNA和靶向光敏剂共负载的肿瘤酸度响应性胶束纳米复合物，用于光动力治疗和免疫治疗的协同整合。该纳米系统被长循环聚乙二醇（PEG）壳包覆，其可以响应于弱酸性肿瘤微环境而脱落，并导致显著的尺寸减小和正电荷增加。这些转变促进纳米载体对肿瘤的渗透和摄取。随后，在温和的酸性内/溶酶体条件下，胶束纳米复合物迅速质子化并崩解，通过海绵效应释放PD-L1阻断siRNA和光敏剂。体外和体内实验的结果共同表明，该纳米系统有效地激活了光动力疗法诱导的免疫应答，并沉默了由检查点基因PD-L1介导的免疫抵抗。因此，通过触发全身抗肿瘤免疫应答抑制黑色素瘤生长并降低复发率。这项研究为开发有效的抗肿瘤免疫治疗提供了一种替代策略。
The checkpoint blockade-based immunotherapy has recently emerged as a promising approach for tumor treatment, but its clinical implementation has been impeded by poor tumor penetration of the nanocarriers and activation of antitumor immune response. To overcome the obstacles, a tumor acidity-responsive micellar nanocomplex co-loaded with programmed death-ligand 1 (PD-L1)-blockade siRNA and mitochondrion-targeting photosensitizer for the synergistic integration of photodynamic therapy and immunotherapy is reported in the present study. The nanosystem is coated with long-circulating polyethylene glycol (PEG) shells, which can be shed in response to the weakly acidic tumor microenvironment and lead to significant size reduction and increasing positive charge. These transitions facilitate penetration and uptake of nanocarriers against tumors. Subsequently, under the mild acidic endo/lysosome condition, the micellar nanocomplexes are rapidly protonated and disintegrated to release the PD-L1-blockade siRNA and photosensitizer through sponge effect. Results from in vitro and in vivo experiments collectively reveal that the nanosystem efficiently activates a photodynamic therapy-induced immune response and silences immune resistance mediated by the checkpoint gene PD-L1. In consequence, melanoma growth is inhibited and the recurrence rate is reduced via triggering systemic antitumor immune responses. This study offers an alternative strategy for the development of efficient antitumor immune therapy.