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Genome-Editing-Mediated Restructuring of Tumor Immune Microenvironment for Prevention of Metastasis
Dongyoon Kim, Yina Wu, Gayong Shim (*co-corresponding), and Yu-Kyoung Oh

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-β (TGF-β) 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-β 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-γ 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-β gene editing and phototherapy is herein supported as a modality for restructuring the tumor immune microenvironment and preventing tumor recurrence.

KEYWORDS: tumor immune microenvironment, metal-lipid hybrid nanoparticle, gene editing, transforming growth factor-β, metastasis