Nature Communications (Sep 2024)

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,
  • Yongjun Liu

DOI
https://doi.org/10.1038/s41467-024-52500-5
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 20

Abstract

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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.