STING Activator c-di-GMP-Loaded Mesoporous Silica Nanoparticles Enhance Immunotherapy against Breast Cancer

Yi Ping Chen, Li Xu, Tao Wei Tang, Cheuh Hsuan Chen, Quan Hong Zheng, Tsang Pai Liu, Chung Yuan Mou, Cheng Hsun Wu, Si Han Wu

Research output: Contribution to journalArticlepeer-review

Abstract

Reversing the immunosuppressive tumor microenvironment (TME) is a strategic initiative to sensitize cancer immunotherapy. Emerging evidence shows that cyclic diguanylate monophosphate (c-di-GMP or cdG) can induce the stimulator of interferon genes (STING) pathway activation of antigen-presenting cells (APCs) and upregulate expression of type I interferons (IFNs) to enhance tumor immunogenicity. In vitro anionic cdG revealed fast plasma clearance, poor membrane permeability, and inadequate cytosolic bioavailability. Therefore, we explored a comprehensive "in situ vaccination"strategy on the basis of nanomedicine to trigger robust antitumor immunity. Rhodamine B isothiocyanate (RITC) fluorescent mesoporous silica nanoparticles (MSN) synthesized and modified with poly(ethylene glycol) (PEG) and an ammonium-based cationic molecule (TA) were loaded with negatively charged cdG via electrostatic interactions to form cdG@RMSN-PEG-TA. Treatment of RAW 264.7 cells with cdG@RMSN-PEG-TA markedly stimulated the secretion of IL-6, IL-1β, and IFN-β along with phospho-STING (Ser365) protein expression. In vivo cdG@RMSN-PEG-TA enhanced infiltration of leukocytes, including CD11c+ dendritic cells, F4/80+ macrophages, CD4+ T cells, and CD8+ T cells within the tumor microenvironment (TME), resulting in dramatic tumor growth inhibition in 4T1 breast tumor-bearing Balb/c mice. Our findings suggest that a nanobased platform can overcome the obstacles bare cdG can face in the TME. Our approach of an in situ vaccination using a STING agonist provides an attractive immunotherapy-based strategy for treating breast cancer.

Original languageEnglish
Pages (from-to)56741-56752
Number of pages12
JournalACS Applied Materials and Interfaces
Volume12
Issue number51
DOIs
Publication statusPublished - Dec 23 2020

Keywords

  • cancer immunotherapy
  • cyclic diguanylate monophosphate
  • in situ vaccination
  • mesoporous silica nanoparticles
  • tumor microenvironment

ASJC Scopus subject areas

  • Materials Science(all)

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