Peptide nanotube loaded with a STING agonist,c-di-GMP,enhance cancer immunotherapy against melanoma  

作　　者：Ziyuan Zhang Juan Liu Min Xiao Quanfeng Zhang Zhonghua Liu Meiyan Liu Peng Zhang Youlin Zeng 

机构地区：[1]Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province,Hunan Normal University,Changsha 410081,China [2]Laboratory of Chemical Biology and Traditional Chinese Medicine Research(Ministry of Education of China),Hunan Normal University,Changsha 410081,China [3]The National&Local Joint Engineering Laboratory of Animal Peptide Drug Development,College of Life Sciences,Hunan Normal University,Changsha 410081,China

出　　处：《Nano Research》2023年第4期5206-5215,共10页纳米研究（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.21877036 and 32201044);the Key Project of Developmental Biology and Breeding from Hunan Province(No.2022XKQ0205);the Hunan Natural Science Foundation(No.2021JJ40335);the Science and Technology Planning Project of Hunan Province(No.2018TP1017).

摘　　要：The activation of the stimulating factor of the interferon gene(STING)pathway can enhance the immune response within the tumor.Cyclic diguanylate monophosphate(c-di-GMP)is a negatively charged,hydrophilic STING agonist,however,its effectiveness is limited due to the poor membrane permeability and low bioavailability.Herein,we introduced KL-7 peptide derived from Aβamyloid fibrils that can self-assemble to form nanotubes to load and deliver c-di-GMP,which significantly enhanced c-di-GMP’s effectiveness and then exhibited a robust“in situ immunity”to kill melanoma cells.KL-7 peptide nanotube,also called PNT,was loaded with negatively charged c-di-GMP via electrostatic interaction,which prepared a nanocomposite named c-di-GMP-PNT.Treatment of RAW 264.7 cells(leukemia cells in mouse macrophage)with c-di-GMP-PNT markedly stimulated the secretion of IL-6 and INF-βalong with phospho-STING(Ser365)protein expression,indicating the activation of the STING pathway.In the unilateral flank B16-F10(murine melanoma cells)tumor-bearing mouse model,compared to PNT and cdi-GMP,c-di-GMP-PNT can promote the expression of INF-β,TNF-α,IL-6,and IL-1β.At the same time,up-regulated CD4 and CD8 active T cells kill tumors and enhance the immune response in tumor tissues,resulting in significant inhibition of tumor growth in tumor-bearing mice.More importantly,in a bilateral flank B16-F10 tumor model,both primary and distant tumor growth can also be significantly inhibited by c-di-GMP-PNT.Moreover,c-di-GMP-PNT demonstrated no obvious biological toxicity on the main organs(heart,liver,spleen,lung,and kidney)and biochemical indexes of mice.In summary,our study provides a strategy to overcome the barriers of free c-di-GMP in the tumor microenvironment and c-di-GMP-PNT may be an attractive nanomaterial for anti-tumor immunity.

关 键 词：cyclic diguanylate monophosphate stimulating factor of the interferon gene(STING) peptide nanotubes in situ immunity tumor immunotherapy 

分 类 号：R739.5[医药卫生—肿瘤] R730.51[医药卫生—临床医学]