期刊
ADVANCED THERAPEUTICS
卷 4, 期 8, 页码 -出版社
WILEY
DOI: 10.1002/adtp.202100065
关键词
cancer immunotherapy; manganese phosphate nanocluster; STING agonist
资金
- Swiss National Science Foundation (SNSF) [315230_173243]
- Swiss Cancer League [KFS-4600-08-2018]
- European Research Council under the ERC [805337]
- Kristian Gerhard Jebsen Foundation
- Ecole Polytechnique Federale de Lausanne (EPFL)
- China Scholarship Council (CSC) [201700260266, 201808320453]
- Eurotech Postdoctoral Programme
- European Commission [754462]
- European Union [754354]
- Ghent University - Special Research Found (BOF) postdoctoral fellowship
- FWO
- European Research Council (ERC) [805337] Funding Source: European Research Council (ERC)
The newly developed MnP-PEG nanoclusters with high biocompatibility can activate immature bone marrow-derived dendritic cells, leading to significantly higher production of interferon beta and interleukin-6. This potent STING activation capacity is likely due to the efficient cellular internalization of MnP-PEG nanoclusters by dendritic cells and acid-triggered release of Mn2+ ions in endolysosomes.
Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), the natural STING agonists, is a promising immunotherapeutic strategy for cancer. However, the clinical application of natural CDNs as therapeutics is greatly hindered by their intrinsic properties including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. Mn2+ ions have been recently discovered to directly activate the cyclic GMP-AMP (cGAMP) synthase (cGAS) and augment cGAMP-STING binding affinity. Here, a PEGylated manganese(II) phosphate (MnP-PEG) nanocluster is developed with high biocompatibility and potent capacity to stimulate the cGAS-STING pathway. MnP-PEG nanoclusters activate the immature bone marrow-derived dendritic cells (DCs) leading to 57.3- and 13.3-fold higher production of interferon beta and interleukin-6 than free cGAMP, respectively. The potent STING activation capacity is likely due to the efficient cellular internalization of MnP-PEG nanoclusters by DCs and acid-triggered release of Mn2+ ions in the endolysosomes. Intratumoral administration of MnP-PEG nanoclusters markedly enhances tumor infiltration as well as maturation of DCs and macrophages, and promotes activation and cytotoxicity of T cells and natural killer cells in the tumor. MnP-PEG nanocluster in combination with a checkpoint inhibitor leads to significant tumor regression in the B16F10 murine melanoma model without any overt toxicities.
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