Research Center of Analytical Instrumentation, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences , Sichuan University , Chengdu 610064 , P. R China.
ACS Appl Mater Interfaces. 2019 Dec 18;11(50):46479-46489. doi: 10.1021/acsami.9b15874. Epub 2019 Dec 5.
DNA nanostructure-based drug delivery system (DDS) has become an advanced therapeutic strategy for cancer because of its unsurpassed editability, intrinsic biodegradability, and tunable multifunctionality. An intelligent DNA nanosystem integrating targeting, immunostimulation, and chemotherapy was constructed based on unmethylated cytosine-phosphate-guanine oligonucleotides (CpG ODNs) DNA nanohydrogels (CpG-MUC1-hydrogel). By facile one-step self-assembly, the cross-shaped DNAs (C-DNAs) assembled from pH-responsive I-motif sequences and targeted MUC1 aptamer-immunoadjuvant CpG-fused sequences (CpG-MUC1) were integrated into DNA nanohydrogels with controllable size by the hybridization of DNA linkers. Subsequently, DOX was successively intercalated into the base pairs of CpG-MUC1-hydrogel, resulting in CpG-MUC1-hydrogel/Dox that would disassemble and release DOX and CpGs at acidic conditions. After MUC1-mediated internalization, CpG-MUC1-hydrogel/Dox dissociated in the endo/lysosomes and induced favorable apoptosis of tumor cells. Afterward, liberated CpGs triggered vast cytokine secretion from immune cells which elicited potent immune response against malignancy. Notably, CpG-MUC1-hydrogel induced an apoptosis effect on MCF-7 cells via significantly increasing the Bax/Bcl ratios and a higher level of tumor necrosis factor (TNF-α) on RAW264.7 cells than naked CpGs. Our results demonstrated that self-assembled CpG-MUC1-hydrogel represented an attractive DDS for precise delivery, potent immunostimulating activity, and considerable combination efficiency with few adverse effects, which is expected to make breakthroughs in clinical translation.
基于 DNA 纳米结构的药物传递系统（DDS）由于其无与伦比的编辑性、内在的生物降解性和可调节的多功能性，已成为癌症的一种先进治疗策略。基于未甲基化胞嘧啶-磷酸-鸟嘌呤寡核苷酸（CpG ODNs）DNA 纳米水凝胶（CpG-MUC1-水凝胶）构建了一种智能 DNA 纳米系统，该系统集成了靶向、免疫刺激和化学疗法。通过简便的一步自组装，由 pH 响应的 I 型结构序列和靶向 MUC1 适体-免疫佐剂 CpG 融合序列（CpG-MUC1）组装的十字形 DNA（C-DNA）通过 DNA 接头的杂交以可控的尺寸集成到 DNA 纳米水凝胶中。随后，DOX 被连续插入到 CpG-MUC1-水凝胶的碱基对中，导致 CpG-MUC1-水凝胶/DOX 在酸性条件下解体并释放 DOX 和 CpGs。在 MUC1 介导的内化后，CpG-MUC1-水凝胶/DOX 在内涵体/溶酶体中解离，并诱导肿瘤细胞发生有利的细胞凋亡。随后，释放的 CpGs 从免疫细胞中引发大量细胞因子的分泌，从而引发针对恶性肿瘤的强烈免疫反应。值得注意的是，与裸露的 CpGs 相比，CpG-MUC1-水凝胶通过显著增加 Bax/Bcl 比值和 RAW264.7 细胞中更高水平的肿瘤坏死因子（TNF-α）对 MCF-7 细胞产生凋亡作用。我们的研究结果表明，自组装的 CpG-MUC1-水凝胶作为一种有吸引力的 DDS，具有精确的递药作用、强大的免疫刺激活性以及与很少的不良反应相当的组合效率，有望在临床转化方面取得突破。
