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

Nano Research 2023年第4期16卷 5206-5215页

作者： Ziyuan Zhang Juan Liu Min Xiao Quanfeng Zhang Zhonghua Liu Meiyan Liu Peng Zhang Youlin Zeng Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province Hunan Normal UniversityChangsha 410081China Laboratory of Chemical Biology and Traditional Chinese Medicine Research(Ministry of Education of China) Hunan Normal UniversityChangsha 410081China The National&Local Joint Engineering Laboratory of Animal Peptide Drug Development College of Life SciencesHunan Normal UniversityChangsha 410081China

The activation of the stimulating factor of the interferon gene(STING)pathway can enhance the immune response within the *** 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 ***,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 ***-7 peptide nanotube,also called PNT,was loaded with negatively charged c-di-GMP via electrostatic interaction,which prepared a nanocomposite named *** 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 *** 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 *** 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 demonstrated no obvious biological toxicity on the main organs(heart,liver,spleen,lung,and kidney)and biochemical indexes of *** 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

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