Self-Assembly of a Multifunction DNA Tetrahedron for Effective Delivery of Aptamer PL1 and Pcsk9 siRNA Potentiate Immune Checkpoint Therapy for Colorectal Cancer.
Self-Assembly of a Multifunction DNA Tetrahedron for Effective Delivery of Aptamer PL1 and Pcsk9 siRNA Potentiate Immune Checkpoint Therapy for Colorectal Cancer.
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DOI：
10.1021/acsami.2c06001
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发表时间：
2022-07-20
影响因子：
9.5
通讯作者：
Han, Anjia
中科院分区：
文献类型：
--
作者：
Guo, Wenjing;Gao, Huabin;Li, Hui;Ge, Songhan;Zhang, Fenfen;Wang, Liyuan;Shi, Huijuan;Han, Anjia
与传统的单一治疗相比，纳米医学促进了多种肿瘤的多模式联合治疗，特别是基于先进的DNA纳米技术开发相应的智能多功能生物材料在癌症联合治疗方面具有巨大的潜力。在这里，我们描述了一种“背包”适配子PL1的策略，它通过DNA杂交与PD-L1和PCSK9 siRNA在定义良好的DNA四面体纳米颗粒(TDN)上特异性结合，共同有助于结直肠癌(CRC)的有效治疗。此外，我们设计了一种基于叶酸(FA)识别的靶向TDN，将其释放限制在遇到叶酸受体(FAR)的肿瘤部位。结果表明，TDN-FA/PL1/PCSK9-siRNA可释放免疫细胞靶向结直肠癌细胞，抑制CT26结直肠癌小鼠肿瘤生长达83.48%。在机制上，靶向FA引导TdN-FA/PL1/PCSK9-siRNA进入肿瘤细胞，从而确保适体PL1能够阻断PD-1和PD-L1之间的相互作用，进而通过PD-1/PD-L1途径使T细胞数量增加1.69倍，T细胞活性抑制1.9倍，而PCSK9siRNA平均使PCSK9的表达降低65.13%，从而促进干扰素-γ和颗粒酶B的强大细胞毒T细胞在瘤内的渗透。我们的结果表明，多功能TND-FA/PL1/PCSK9-siRNA用于结直肠癌治疗是有效和安全的，从而扩大了DNA纳米技术在各种癌症创新治疗中的应用。
Compared with the traditional single therapy, nanomedicine has promoted a multimodal combination treatment for various carcinomas, especially the development of corresponding intelligent multifunctional biomaterials based on advanced DNA nanotechnology has great potential in cancer combination therapy. Herein, we describe a strategy to “backpack” aptamer PL1, which specifically binds to PD-L1 and Pcsk9 siRNA on well-defined DNA tetrahedral nanoparticles (TDNs) via DNA hybridization, which collectively contributes to the effective therapy for colorectal cancer (CRC). In addition, we designed a targeted TDN upon folic acid (FA) recognition, limiting its release to the sites of tumors where folic acid receptor (FAR) is encountered. Our results demonstrated that the TDN-FA/PL1/Pcsk9-siRNA could free immune cells to target CRC cells and attenuate 83.48% tumor growth in mouse models of CT26 CRC. Mechanically, the cancer-targeting FA guided TDN-FA/PL1/Pcsk9-siRNA into tumor cells, thereby ensuring that the aptamer PL1 could choke the mutual effects between PD-1 and PD-L1, followed by a 1.69-fold increase in T cell number and a 1.9-fold suppression of T cell activity by the PD-1/PD-L1 pathway, while Pcsk9 siRNA decreased Pcsk9 expression averagely to the extent of 65.13% and then facilitated intratumoral infiltration of cytotoxic T cells robustly with IFN-γ and Granzyme B expression. Our results reveal that the multifunctional TND-FA/PL1/Pcsk9-siRNA is effective and safe for CRC therapy, thereby expanding the application of DNA nanotechnology for innovative therapies of various cancers.
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DOI：
10.1016/s1470-2045(16)30053-5
发表时间：
2016-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Goldberg SB;Gettinger SN;Mahajan A;Chiang AC;Herbst RS;Sznol M;Tsiouris AJ;Cohen J;Vortmeyer A;Jilaveanu L;Yu J;Hegde U;Speaker S;Madura M;Ralabate A;Rivera A;Rowen E;Gerrish H;Yao X;Chiang V;Kluger HM
通讯作者：
Kluger HM
影响因子：
9.5
作者：
Qu, Yijiao;Yang, Juanjuan;Ding, Baoquan
通讯作者：
Ding, Baoquan
影响因子：
6.7
作者：
Sacks, David;Baxter, Blaise;Vorwerk, Dierk
通讯作者：
Vorwerk, Dierk
影响因子：
38.3
作者：
通讯作者：
--
影响因子：
10.8
作者：
Maeda, H;Wu, J;Hori, K
通讯作者：
Hori, K