Effective delivery of STING agonist using exosomes suppresses tumor growth and enhances antitumor immunity.
Effective delivery of STING agonist using exosomes suppresses tumor growth and enhances antitumor immunity.
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使用外泌体有效递送刺激激动剂可抑制肿瘤的生长并增强抗肿瘤免疫力。
DOI：
10.1016/j.jbc.2021.100523
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Kalluri R
中科院分区：
文献类型：
--
作者：
McAndrews KM;Che SPY;LeBleu VS;Kalluri R
干扰素基因刺激因子（STING）通路与先天免疫应答有关，在肿瘤发生和癌症治疗中都很重要。具体地，抗原呈递细胞（APC）中的胞质DNA传感器STING的激活诱导促进抗肿瘤免疫治疗的I型干扰素应答和细胞因子产生。然而，STING激动剂（STINGa）作为癌症治疗剂的使用受到不利的药理学性质和靶向效率的限制，这是由于快速清除和有限的细胞溶质摄取。外泌体是一类由所有细胞脱落的细胞外囊泡，由于其被细胞吸收的先天能力和其用于最佳药物生物分布的生物相容性，它们被考虑用作药物的有效载体。因此，我们工程化外泌体以递送STING激动剂环GMP-AMP（iExoSTINGa），以利用其有利的药代动力学和药效学。与单独的STINGa相比，iExoSTINGa选择性靶向APC中的STING途径与抑制B16 F10肿瘤生长的上级效力相关。此外，与单独的STINGa相比，iExoSTINGa显示STINGa进入树突细胞的上级摄取，这导致活化的CD 8 + T细胞的积累增加和抗肿瘤免疫应答。我们的研究强调了外泌体（特别是iExoSTINGa）在增强癌症治疗结果方面的潜力。
The Stimulator of Interferon Genes (STING) pathway is implicated in the innate immune response and is important in both oncogenesis and cancer treatment. Specifically, activation of the cytosolic DNA sensor STING in antigen-presenting cells (APCs) induces a type I interferon response and cytokine production that facilitates antitumor immune therapy. However, use of STING agonists (STINGa) as a cancer therapeutic has been limited by unfavorable pharmacological properties and targeting inefficiency due to rapid clearance and limited uptake into the cytosol. Exosomes, a class of extracellular vesicles shed by all cells are under consideration for their use as effective carriers of drugs owing to their innate ability to be taken up by cells and their biocompatibility for optimal drug biodistribution. Therefore, we engineered exosomes to deliver the STING agonist cyclic GMP-AMP (iExoSTINGa), to exploit their favorable pharmacokinetics and pharmacodynamics. Selective targeting of the STING pathway in APCs with iExoSTINGa was associated with superior potency compared with STINGa alone in suppressing B16F10 tumor growth. Moreover, iExoSTINGa showed superior uptake of STINGa into dendritic cells compared with STINGa alone, which led to increased accumulation of activated CD8+ T-cells and an antitumor immune response. Our study highlights the potential of exosomes in general, and iExoSTINGa specifically, in enhancing cancer therapy outcomes.
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DOI：
10.1016/j.jconrel.2015.07.030
发表时间：
2015-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Batrakova EV;Kim MS
通讯作者：
Kim MS
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
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影响因子：
8
作者：
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通讯作者：
Kalluri, Raghu
DOI：
10.1038/nri3622
发表时间：
2014-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
Gentili, Matteo;Kowal, Joanna;Manel, Nicolas
通讯作者：
Manel, Nicolas