Liu Jing, Li Hong-Jun, Luo Ying-Li, Chen Yi-Fang, Fan Ya-Nan, Du Jin-Zhi, Wang Jun
Guangzhou First People's Hospital, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, P. R. China.
School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P. R. China.
Nano Lett. 2020 Jul 8;20(7):4882-4889. doi: 10.1021/acs.nanolett.0c00893. Epub 2020 Jun 23.
Tumor-infiltrating dendritic cells (TIDCs) are mostly immature and immunosuppressive, usually mediating immune inhibition. The utilization of cytosine-guanine oligodeoxynucleotides (CpG ODNs) to stimulate the activation of TIDCs has been demonstrated to be effective for improving antitumor immunity. However, a series of biological barriers has limited the efficacy of previous nanocarriers for delivering CpG to TIDCs. Herein, we developed a dual-sensitive dendrimer cluster-based nanoadjuvant for delivering CpG ODNs into TIDCs. We show that the tumor acidity triggers the rapid release of CpG conjugated polyamidoamine (PAMAM) dendrimers from the nanoadjuvant, thus facilitating its perfusion deep into tumors and phagocytosis by TIDCs. Thereafter, the reductive condition of the endolysosomes led to the subsequent release of CpG, which promotes the DCs activation and enhances antitumor immunotherapies. Programmable delivery of immune adjuvant efficiently overcomes the barriers for targeted delivery to TIDCs and provides a promising strategy for improving cancer immunotherapy.
肿瘤浸润性树突状细胞（TIDCs）大多不成熟且具有免疫抑制作用，通常介导免疫抑制。利用胞嘧啶-鸟嘌呤寡脱氧核苷酸（CpG ODNs）刺激TIDCs的活化已被证明对提高抗肿瘤免疫力有效。然而，一系列生物学障碍限制了先前纳米载体将CpG递送至TIDCs的功效。在此，我们开发了一种基于双敏感树枝状聚合物簇的纳米佐剂，用于将CpG ODNs递送至TIDCs。我们表明，肿瘤酸性环境触发纳米佐剂中与CpG偶联的聚酰胺-胺（PAMAM）树枝状聚合物的快速释放，从而促进其深入肿瘤灌注并被TIDCs吞噬。此后，内溶酶体的还原环境导致CpG随后释放，这促进了树突状细胞的活化并增强了抗肿瘤免疫疗法。免疫佐剂的可编程递送有效克服了靶向递送至TIDCs的障碍，并为改善癌症免疫疗法提供了一种有前景的策略。
