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.

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。