Bacterial protoplast-derived nanovesicles carrying CRISPR-Cas9 tools re-educate tumor-associated macrophages for enhanced cancer immunotherapy.
Bacterial protoplast-derived nanovesicles carrying CRISPR-Cas9 tools re-educate tumor-associated macrophages for enhanced cancer immunotherapy.
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携带CRISPR-Cas9工具的细菌原生质体衍生的纳米囊泡可以重新培养肿瘤相关的巨噬细胞，以加强癌症免疫治疗。
DOI：
10.1038/s41467-024-44941-9
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发表时间：
2024-01-31
影响因子：
16.6
通讯作者：
Zhang, Junfeng
中科院分区：
文献类型：
--
作者：
Zhao, Mingming;Cheng, Xiaohui;Shao, Pingwen;Dong, Yao;Wu, Yongjie;Xiao, Lin;Cui, Zhiying;Sun, Xuedi;Gao, Chuancheng;Chen, Jiangning;Huang, Zhen;Zhang, Junfeng
CRISPR-Cas9系统通过精确操纵参与肿瘤发生和免疫反应的关键基因，为癌症治疗提供了巨大的潜力。尽管前景看好，但该系统面临着严峻的挑战，包括编辑后细胞活力的保持和确保体内安全递送。为了解决这些问题，本研究开发了一种靶向肿瘤相关巨噬细胞（TAM）的体内CRISPR-Cas9系统。我们采用细菌原生质体衍生的纳米囊泡（NV）与pH值响应PEG共轭磷脂衍生物和半乳糖胺共轭磷脂衍生物的TAM靶向修改。利用质粒转化E.大肠杆菌原生质体作为生产平台，我们成功地用两个关键组分加载了NV：靶向Pik3cg的Cas9-sgRNA核糖核蛋白，这是巨噬细胞极化的关键分子开关，以及细菌富含CpG的DNA片段，作为有效的TLR9配体。这种基于NV的自组装方法显示出可扩展临床生产的前景。我们的策略通过稳定TAM中的M1样表型来重塑肿瘤微环境，从而抑制雌性小鼠的肿瘤生长。这种体内CRISPR-Cas9技术为癌症免疫治疗开辟了途径，克服了与细胞活力和安全、精确的体内递送相关的挑战。CRISPR-Cas9基因组编辑系统在癌症治疗中具有巨大的潜力。在这里，作者报告了一种使用源自E.大肠杆菌原生质体以封装Cas9-sgRNA核糖核蛋白，用于选择性靶向肿瘤相关巨噬细胞中的Pik3cg。
The CRISPR-Cas9 system offers substantial potential for cancer therapy by enabling precise manipulation of key genes involved in tumorigenesis and immune response. Despite its promise, the system faces critical challenges, including the preservation of cell viability post-editing and ensuring safe in vivo delivery. To address these issues, this study develops an in vivo CRISPR-Cas9 system targeting tumor-associated macrophages (TAMs). We employ bacterial protoplast-derived nanovesicles (NVs) modified with pH-responsive PEG-conjugated phospholipid derivatives and galactosamine-conjugated phospholipid derivatives tailored for TAM targeting. Utilizing plasmid-transformed E. coli protoplasts as production platforms, we successfully load NVs with two key components: a Cas9-sgRNA ribonucleoprotein targeting Pik3cg, a pivotal molecular switch of macrophage polarization, and bacterial CpG-rich DNA fragments, acting as potent TLR9 ligands. This NV-based, self-assembly approach shows promise for scalable clinical production. Our strategy remodels the tumor microenvironment by stabilizing an M1-like phenotype in TAMs, thus inhibiting tumor growth in female mice. This in vivo CRISPR-Cas9 technology opens avenues for cancer immunotherapy, overcoming challenges related to cell viability and safe, precise in vivo delivery. CRISPR-Cas9 genome editing systems have great potential in cancer therapy. Here the authors report a gene-editing delivery system using functionalized nanovesicles derived from E. coli protoplasts to encapsulate Cas9-sgRNA ribonucleoprotein for the selective targeting of Pik3cg in tumor associated macrophages.
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影响因子：
120.1
作者：
Foy, Susan P. P.;Jacoby, Kyle;Bota, Daniela A. A.;Hunter, Theresa;Pan, Zheng;Stawiski, Eric;Ma, Yan;Lu, William;Peng, Songming;Wang, Clifford L. L.;Yuen, Benjamin;Dalmas, Olivier;Heeringa, Katharine;Sennino, Barbara;Conroy, Andy;Bethune, Michael T. T.;Mende, Ines;White, William;Kukreja, Monica;Gunturu, Swetha;Humphrey, Emily;Hussaini, Adeel;An, Duo;Litterman, Adam J. J.;Quach, Boi Bryant;Ng, Alphonsus H. C.;Lu, Yue;Smith, Chad;Campbell, Katie M. M.;Anaya, Daniel;Skrdlant, Lindsey;Huang, Eva Yi-Hsuan;Mendoza, Ventura;Mathur, Jyoti;Dengler, Luke;Purandare, Bhamini;Moot, Robert;Yi, Michael C. C.;Funke, Roel;Sibley, Alison;Stallings-Schmitt, Todd;Oh, David Y. Y.;Chmielowski, Bartosz;Abedi, Mehrdad;Yuan, Yuan;Sosman, Jeffrey A. A.;Lee, Sylvia M. M.;Schoenfeld, Adam J. J.;Baltimore, David;Heath, James R. R.;Franzusoff, Alex;Ribas, Antoni;Rao, Arati V. V.;Mandl, Stefanie J. J.
通讯作者：
Mandl, Stefanie J. J.
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
影响因子：
14.9
作者：
Chen T;Ma J;Liu Y;Chen Z;Xiao N;Lu Y;Fu Y;Yang C;Li M;Wu S;Wang X;Li D;He F;Hermjakob H;Zhu Y
通讯作者：
Zhu Y
工程细菌膜纳米层可改善传染病和癌症的疗法。
影响因子：
16.1
作者：
通讯作者：
--
生物工程细菌衍生的外膜囊泡作为多功能抗原展示平台，通过即插即用技术进行肿瘤疫苗接种
影响因子：
16.6
作者：
Cheng K;Zhao R;Li Y;Qi Y;Wang Y;Zhang Y;Qin H;Qin Y;Chen L;Li C;Liang J;Li Y;Xu J;Han X;Anderson GJ;Shi J;Ren L;Zhao X;Nie G
通讯作者：
Nie G