期刊
NANOSCALE HORIZONS
卷 6, 期 2, 页码 156-167出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0nh00446d
关键词
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资金
- National Cancer Institute [R01CA253627, U01CA198892]
- Case Comprehensive Cancer Center GI SPORE [2P50CA150964-07A1]
- Case Comprehensive Cancer Center Support Grant [P30CA043703]
- Shiverick Family Fund
- Clinical Translational Science Collaborative of Cleveland [UL1TR002548]
- Alex's Lemonade Stand Foundation
- NSF graduate research fellowships program
- NIH Interdisciplinary Biomedical Imaging Training Program [T32EB007509]
The study focused on using an immunostimulatory mesoporous silica nanoparticle, termed immuno-MSN, to boost the local innate immune compartment of GBM and enhance the antitumor immune response, resulting in elevated pro-inflammatory effects.
The high mortality associated with glioblastoma multiforme (GBM) is attributed to its invasive nature, hypoxic core, resistant cell subpopulations and a highly immunosuppressive tumor microenvironment (TME). To support adaptive immune function and establish a more robust antitumor immune response, we boosted the local innate immune compartment of GBM using an immunostimulatory mesoporous silica nanoparticle, termed immuno-MSN. The immuno-MSN was specifically designed for systemic and proficient delivery of a potent innate immune agonist to dysfunctional antigen-presenting cells (APCs) in the brain TME. The cargo of the immuno-MSN was cyclic diguanylate monophosphate (cdGMP), a Stimulator of Interferon Gene (STING) agonist. Studies showed the immuno-MSN promoted the uptake of STING agonist by APCs in vitro and the subsequent release of the pro-inflammatory cytokine interferon beta, 6-fold greater than free agonist. In an orthotopic GBM mouse model, systemically administered immuno-MSN particles were taken up by APCs in the near-perivascular regions of the brain tumor with striking efficiency. The immuno-MSNs facilitated the recruitment of dendritic cells and macrophages to the TME while sparing healthy brain tissue and peripheral organs, resulting in elevated circulating CD8(+) T cell activity (2.5-fold) and delayed GBM tumor growth. We show that an engineered immunostimulatory nanoparticle can support pro-inflammatory innate immune function in GBM and subsequently augment current immunotherapeutic interventions and improve their therapeutic outcome.
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