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Genome-Editing-Mediated Restructuring of Tumor Immune Microenvironment for Prevention of Metastasis

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Issue Date
2021-11
Publisher
AMER CHEMICAL SOC
Citation
ACS NANO, Vol.15 No.11, pp.17635-17656
Abstract
Modulating the tumor immune microenvironment to activate immune cells has been investigated to convert cold to hot tumors. Here, we report that metal-lipid hybrid nanoparticle (MLN)-mediated gene editing of transforming growth factor-beta (TGF-beta) can restructure the tumor microenvironment to an "immune activated" state for subsequent immunotherapy. MLNs with cationic lipids and elemental metallic Au inside were designed to deliver plasmid DNA encoding TGF-beta single guide RNA and Cas9 protein (pC9sTgf) and to convert near-infrared light (NIR) to heat. Upon NIR irradiation, MLNs induced photothermal anticancer effects and calreticulin exposure on B16F10 cancer cells. Lipoplexes of pC9sTgf and MLN (pC9sTgf@MLN) provided gene editing of B16F10 cells and in vivo tumor tissues. In mice treated with pC9sTgf@MLNs and NIR irradiation, the tumor microenvironment showed increases in mature dendritic cells, cytotoxic T cells, and interferon-gamma expression. In B16F10 tumor-bearing mice, intratumoral injection of pC9sTgf@MLNs and NIR irradiation resulted in ablation of primary tumors. Application of pC9sTgf@MLNs and NIR irradiation prevented the growth of secondarily challenged B16F10 cells at distant sites and B16F10 lung metastasis. Combined TGF-ss gene editing and phototherapy is herein supported as a modality for restructuring the tumor immune microenvironment and preventing tumor recurrence.
ISSN
1936-0851
URI
https://hdl.handle.net/10371/179775
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College of Pharmacy (약학대학)Dept. of Manufacturing Pharmacy (제약학과)Journal Papers (저널논문_제약학과)
College of Pharmacy (약학대학)Dept. of Manufacturing Pharmacy (제약학과)Journal Papers (저널논문_제약학과)
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