Glypican-3-targeted macrophages delivering drug-loaded exosomes offer efficient cytotherapy in mouse models of solid tumours

Jinhu Liu, Huajun Zhao, Tong Gao, Xinyan Huang, Shujun Liu, Meichen Liu, Weiwei Mu, Shuang Liang, Shunli Fu, Shijun Yuan, Qinglin Yang, Panpan Gu, Nan Li, Qingping Ma, Jie Liu, Xinke Zhang, Na Zhang () and Yongjun Liu ()
Additional contact information
Jinhu Liu: Shandong University
Huajun Zhao: Shandong University
Tong Gao: Shandong University
Xinyan Huang: Shandong University
Shujun Liu: Shandong University
Meichen Liu: Shandong University
Weiwei Mu: Shandong University
Shuang Liang: Shandong University
Shunli Fu: Shandong University
Shijun Yuan: Shandong University
Qinglin Yang: Shandong University
Panpan Gu: Shandong University
Nan Li: Shandong University
Qingping Ma: Shandong University
Jie Liu: Shandong University
Xinke Zhang: Shandong University
Na Zhang: Shandong University
Yongjun Liu: Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Cytotherapy is a strategy to deliver modified cells to a diseased tissue, but targeting solid tumours remains challenging. Here we design macrophages, harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the engineered macrophages, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO). The OMVs facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed RILOs through exosomes. RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment.

Date: 2024
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DOI: 10.1038/s41467-024-52500-5

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