STING Activator c-di-GMP-Loaded Mesoporous Silica Nanoparticles Enhance Immunotherapy Against Breast Cancer
- 11 December 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Applied Materials & Interfaces
- Vol. 12 (51), 56741-56752
- https://doi.org/10.1021/acsami.0c16728
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 [email protected] Treatment of RAW 264.7 cells with [email protected] markedly stimulated the secretion of IL-6, IL-1β, and IFN-β along with phospho-STING (Ser365) protein expression. In vivo [email protected] 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.Funding Information
- Ministry of Science and Technology, Taiwan (MOST 107-2113-M-038-003-MY2, MOST 108-2113-M-002-004, MOST 108-2113-M-038-001-MY2)
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