Bacterial protoplast-derived nanovesicles carrying CRISPR-Cas9 tools re-educate tumor-associated macrophages for enhanced cancer immunotherapy

Mingming Zhao, Xiaohui Cheng, Pingwen Shao, Yao Dong, Yongjie Wu, Lin Xiao, Zhiying Cui, Xuedi Sun, Chuancheng Gao, Jiangning Chen (), Zhen Huang () and Junfeng Zhang ()
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Mingming Zhao: Nanjing University
Xiaohui Cheng: Nanjing University
Pingwen Shao: Nanjing University
Yao Dong: Nanjing University
Yongjie Wu: Nanjing University
Lin Xiao: Nanjing University
Zhiying Cui: Nanjing University
Xuedi Sun: Nanjing University
Chuancheng Gao: Nanjing University
Jiangning Chen: Nanjing University
Zhen Huang: Nanjing University
Junfeng Zhang: Nanjing University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44941-9

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