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

• Published in: ACS applied materials & interfaces 2020-12, Vol.12 (51), p.56741-56752
• Main Authors: Chen, Yi-Ping, Xu, Li, Tang, Tao-Wei, Chen, Cheuh-Hsuan, Zheng, Quan-Hong, Liu, Tsang-Pai, Mou, Chung-Yuan, Wu, Cheng-Hsun, Wu, Si-Han
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; Biological and Medical Applications of Materials and Interfaces; Breast Neoplasms - therapy; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cyclic GMP - analogs & derivatives; Cyclic GMP - pharmacology; Female; Fluorescent Dyes - chemistry; Immunotherapy - methods; Lymphocyte Activation - drug effects; Membrane Proteins - agonists; Mice; Mice, Inbred BALB C; Nanoparticles - chemistry; Porosity; RAW 264.7 Cells; Rhodamines - chemistry; Signal Transduction - drug effects; Silicon Dioxide - chemistry; Tumor Microenvironment - immunology
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.0c16728

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.