Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.
Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.
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DOI：
10.1016/j.jconrel.2022.03.021
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发表时间：
2022-05
影响因子：
10.8
通讯作者：
Dong, Yizhou
中科院分区：
文献类型：
--
作者：
Liu, Jin-Qing;Zhang, Chengxiang;Zhang, Xinfu;Yan, Jingyue;Zeng, Chunxi;Talebian, Fatemeh;Lynch, Kimberly;Zhao, Weiyu;Hou, Xucheng;Du, Shi;Kang, Diana D.;Deng, Binbin;McComb, David W.;Bai, Xue-Feng;Dong, Yizhou
细胞因子是重要的免疫治疗剂，具有用于治疗人类癌症的批准药物。然而，由于剂量限制性毒性，细胞因子的全身施用通常不能达到肿瘤中免疫细胞的足够浓度。因此，开发直接向肿瘤递送免疫刺激性细胞因子的局部治疗可以提高治疗功效。在这项研究中，我们产生了新的脂质纳米粒（LNPs）与编码细胞因子，包括IL-12，IL-27和GM-CSF的mRNA封装，并测试其抗肿瘤活性。我们首先合成了可电离的脂质材料，其含有具有各种头部基团（DALs）的二氨基。新的DAL 4-LNP在体外有效地将不同的mRNA递送至肿瘤细胞和在体内有效地递送至肿瘤。与单一疗法中的IL-27或GM-CSF mRNA相比，瘤内注射负载有IL-12 mRNA的DAL 4-LNP在抑制B16 F10黑色素瘤肿瘤生长方面最有效。此外，肿瘤内注射双重DAL 4-LNP-IL-12 mRNA和IL-27 mRNA在抑制肿瘤生长方面显示出协同效应，而不引起全身毒性。最重要的是，IL-12和IL-27 mRNA的肿瘤内递送诱导免疫效应细胞（包括产生IFN-γ和TNF-α的NK和CD 8 + T细胞）稳健地浸润到肿瘤中。因此，肿瘤内施用负载有IL-12和IL-27 mRNA的DAL-LNP为癌症提供了新的治疗策略。
Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve adequate concentrations to immune cells in tumors due to dose-limiting toxicity. Thus, developing localized therapy that directly delivers immune-stimulatory cytokines to tumors may improve the therapeutic efficacy. In this study, we generated novel lipid nanoparticles (LNPs) encapsulated with mRNAs encoding cytokines including IL-12, IL-27 and GM-CSF, and tested their anti-tumor activity. We first synthesized ionizable lipid materials containing di-amino groups with various head groups (DALs). The novel DAL4-LNP effectively delivered different mRNAs in vitro to tumor cells and in vivo to tumors. Intratumoral injection of DAL4-LNP loaded with IL-12 mRNA was most potent in inhibiting B16F10 melanoma tumor growth compared to IL-27 or GM-CSF mRNAs in monotherapy. Furthermore, intratumoral injection of dual DAL4-LNP-IL-12 mRNA and IL-27 mRNA showed a synergistic effect in suppressing tumor growth without causing systematic toxicity. Most importantly, intratumoral delivery of IL-12 and IL-27 mRNAs induced robust infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8+ T cells into tumors. Thus, intratumoral administration of DAL-LNP loaded with IL-12 and IL-27 mRNA provides a new treatment strategy for cancer.
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影响因子：
11.5
作者：
Bhatia, Shailender;Longino, Natalie V.;Miller, Natalie J.;Kulikauskas, Rima;Iyer, Jayasri G.;Ibrani, Dafina;Blom, Astrid;Byrd, David R.;Parvathaneni, Upendra;Twitty, Christopher G.;Campbell, Jean S.;Le, Mai H.;Gargosky, Sharron;Pierce, Robert H.;Heller, Richard;Daud, Adil I.;Nghiem, Paul
通讯作者：
Nghiem, Paul
DOI：
10.1038/s41578-021-00358-0
发表时间：
2021
期刊：
Nature reviews. Materials
影响因子：
--
作者：
Hou X;Zaks T;Langer R;Dong Y
通讯作者：
Dong Y
影响因子：
4.4
作者：
Fitzgerald, Denise C.;Ciric, Bogoljub;Rostami, Abdolmohamad
通讯作者：
Rostami, Abdolmohamad
影响因子：
11.2
作者：
Hisada, M;Kamiya, S;Yoshimoto, T
通讯作者：
Yoshimoto, T
影响因子：
4.6
作者：
Li B;Luo X;Deng B;Giancola JB;McComb DW;Schmittgen TD;Dong Y
通讯作者：
Dong Y