Journal
NANO RESEARCH
Volume 16, Issue 4, Pages 5206-5215Publisher
TSINGHUA UNIV PRESS
DOI: 10.1007/s12274-022-5102-z
Keywords
cyclic diguanylate monophosphate; STING; peptide nanotubes; in situ immunity; tumor immunotherapy
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By using KL-7 peptide nanotubes to load and deliver c-di-GMP, the study demonstrated enhanced effectiveness of c-di-GMP and its robust in situ immunity against melanoma cells. The c-di-GMP-PNT nanocomposite activated the STING pathway and promoted immune response, resulting in significant inhibition of tumor growth without obvious toxicity.
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 A beta 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-beta 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-beta, TNF-alpha, IL-6, and IL-1 beta. 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.
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