의생명시스템학부 심가용 교수는 종양의 면역회피 기전에 중요한 역할을 하는 TGF beta를 유전자 편집을 통해 발현을 억제하였고 면역세포가 활성화 된 종양미세환경 (tumor microenvironment)에서 금 나노 지질 하이브리드 나노입자를 이용한 광치료를 통해 원발 종양 세포는 물론 전이성 종양 재발을 방지하는 것을 관찰하였다. 이 연구에서 이용된 금 나노 지질 하이브리드 나노입자는 유전자가위의 효과적인 전달은 물론 광치료도 가능한 다기능성 전달플랫폼으로 이용될 수 있을 것으로 기대된다.
이 연구는 서울대학교 오유경교수 연구팀과의 공동 연구를 통해 진행되었으며 나노/의약학 분야의 저명한 SCI 저널인 ACS Nano (IF: 15.881)에 발표되었다. 관련 소식은 BRIC 한국을 빛낸 사람들에도 소개되었다 (한빛사 바로가기).
ACS Nano, Publication Date:November 1, 2021 | https://doi.org/10.1021/acsnano.1c05420
Genome-Editing-Mediated Restructuring of Tumor Immune Microenvironment for Prevention of Metastasis
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-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