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肿瘤穿透性 PEG-脂质纳米盘递送 STING 激动剂可引发强大的抗癌免疫。

STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity.

机构信息

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

Department of Materials, Imperial College London, London, UK.

出版信息

Nat Mater. 2022 Jun;21(6):710-720. doi: 10.1038/s41563-022-01251-z. Epub 2022 May 23.

DOI:10.1038/s41563-022-01251-z
PMID:35606429
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9156412/
Abstract

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.

摘要

先天免疫干扰素基因刺激物 (STING) 途径的激活增强了抗肿瘤免疫，但将 STING 激动剂全身递送至肿瘤具有挑战性。我们通过可裂解接头将 STING 激活的环二核苷酸 (CDN) 缀合到聚乙二醇化脂质 (CDN-PEG-脂质；PEG，聚乙二醇) 上，并将其纳入脂质纳米盘 (LND) 中，LND 是由自组装形成的盘状纳米颗粒。与最先进的脂质体相比，静脉内给予携带 CDN-PEG-脂质的 LND (LND-CDNs) 可更有效地穿透肿瘤，使大多数肿瘤细胞暴露于 STING 激动剂下。单次给予 LND-CDN 可引发已建立的肿瘤排斥反应，同时对肿瘤再挑战产生免疫记忆。尽管 CDN 本身不是直接的杀肿瘤剂，但 LND-CDN 被癌细胞摄取与通过促进 CDN 和肿瘤抗原在树突状细胞中的共定位来强烈激活 T 细胞相关。因此，LND 似乎很有前途，可以作为一种载体，将化合物有效地递送至整个实体瘤中，从而可以用于增强免疫治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/03850f3b50a6/41563_2022_1251_Fig16_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/78f4cfdc68eb/41563_2022_1251_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/03850f3b50a6/41563_2022_1251_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/6070b983d93b/41563_2022_1251_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/cd922e8fa34b/41563_2022_1251_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/937503b64f7d/41563_2022_1251_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/1440abf7bebb/41563_2022_1251_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/c9c86f182980/41563_2022_1251_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/c7197505c68b/41563_2022_1251_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/307d07a27fba/41563_2022_1251_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/cd556f4ffb18/41563_2022_1251_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/848571a531f2/41563_2022_1251_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/cf7fd125b50b/41563_2022_1251_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/da1e58bd1501/41563_2022_1251_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/3acff31fea0b/41563_2022_1251_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/fc2a31a86600/41563_2022_1251_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/65ce6ff0fe98/41563_2022_1251_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/78f4cfdc68eb/41563_2022_1251_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f563/9156412/03850f3b50a6/41563_2022_1251_Fig16_ESM.jpg

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[10]
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