肿瘤细胞治疗研究
英文原题：Glypican-3-targeted macrophages delivering drug-loaded exosomes offer efficient cytotherapy in mouse models of solid tumours.
细胞疗法是一种将修饰细胞递送至病变组织的策略，但靶向实体瘤仍具挑战性。
细胞治疗是一种将修饰细胞递送至病变组织的策略，但靶向实体瘤仍具挑战性。在此，我们设计了巨噬细胞，其表面带有靶向glypican-3的肽，并携带用于对抗实体瘤的货物。锚定的靶向肽促进工程化巨噬细胞对肿瘤细胞的识别，从而增强对表达glypican-3的肿瘤细胞的特异性靶向和吞噬作用。这些巨噬细胞携带TLR7/TLR8激动剂R848和INCB024360（一种选择性吲哚胺2,3-双加氧酶1（IDO1）抑制剂）的货物，包裹在来源于大肠杆菌的C16-神经酰胺融合外膜囊泡（OMV）中（RILO）。OMV通过小窝蛋白介导的内吞作用促进内化，并且为了维持合适的纳米结构，C16-神经酰胺诱导膜内陷和外泌体生成，导致通过外泌体释放装载货物的RILO。负载RILO的巨噬细胞在携带H22肝细胞癌（高表达glypican-3）的小鼠中发挥治疗效果。总体而言，我们为靶向实体瘤的细胞治疗策略奠定了原理验证，并可能补充常规治疗。
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.
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