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STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity
Nature Materials ( IF 37.2 ) Pub Date : 2022-05-23 , DOI: 10.1038/s41563-022-01251-z
Eric L Dane 1 , Alexis Belessiotis-Richards 2, 3, 4 , Coralie Backlund 1 , Jianing Wang 5 , Kousuke Hidaka 6 , Lauren E Milling 1, 7 , Sachin Bhagchandani 1, 8 , Mariane B Melo 1 , Shengwei Wu 1 , Na Li 1 , Nathan Donahue 1 , Kaiyuan Ni 1 , Leyuan Ma 1 , Masanori Okaniwa 9 , Molly M Stevens 2, 3, 4 , Alfredo Alexander-Katz 10 , Darrell J Irvine 1, 7, 10, 11, 12
Affiliation  

Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.



中文翻译:

通过肿瘤穿透性 PEG-脂质纳米盘传递 STING 激动剂可增强强大的抗癌免疫力

先天免疫干扰素基因刺激剂 (STING) 途径的激活可增强抗肿瘤免疫,但将 STING 激动剂全身递送至肿瘤具有挑战性。我们通过可裂解连接体将 STING 激活环状二核苷酸 (CDN) 与聚乙二醇化脂质 (CDN-PEG-脂质;PEG,聚乙二醇) 结合,并将它们整合到脂质纳米盘 (LND) 中,脂质纳米盘是通过自组装形成的盘状纳米颗粒。与最先进的脂质体相比,静脉注射携带 CDN-PEG-脂质 (LND-CDN) 的 LND 表现出更有效的肿瘤渗透,使大多数肿瘤细胞暴露于 STING 激动剂。单剂量的 LND-CDN 诱导对已形成肿瘤的排斥,这与针对肿瘤再攻击的免疫记忆相一致。尽管 CDN 不能直接杀伤肿瘤,但癌细胞对 LND-CDN 的摄取通过促进 CDN 和肿瘤抗原在树突状细胞中的共定位而与 T 细胞的强力激活相关。因此,LND 作为一种在实体瘤中强有力地递送化合物的载体似乎很有前景,可用于增强免疫治疗。

更新日期:2022-05-24
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