@article{Zhang2023, 
author = {Ziyuan Zhang and Juan Liu and Min Xiao and Quanfeng Zhang and Zhonghua Liu and Meiyan Liu and Peng Zhang and Youlin Zeng},
title = {Peptide nanotube loaded with a STING agonist, c-di-GMP, enhance cancer immunotherapy against melanoma},
year = {2023},
journal = {Nano Research},
volume = {16},
number = {4},
pages = {5206-5215},
keywords = {cyclic diguanylate monophosphate, stimulating factor of the interferon gene (STING), peptide nanotubes, in situ immunity, tumor immunotherapy},
url = {https://www.sciopen.com/article/10.1007/s12274-022-5102-z},
doi = {10.1007/s12274-022-5102-z},
abstract = {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 Aβ amyloid 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-β along 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 c-di-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.}
}