Engineered NK92 cell-derived exosomes inhibit ovarian cancer progression by degrading GPRC5A

作者：Chaohua Si, Yihan Wang, Yuanyuan Li, Yuqi Chen, Yuxuan Fan, Yunwen Wang, Yanan Tian, Jianen Gao, Xu Ma · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1613178 · 被引用次数：6 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Circular RNAs in diseases

Background Natural killer (NK) 92 (NK92) cells are critical immune-effectors with established roles in treating metastatic and hematological malignancies. Owing to the substantial adverse effects, including cytokine release syndrome, associated with NK92 cell therapy, research interest has pivoted toward the safer and potentially more efficient exosome-based approaches. However, the composition, properties, and functions of NK92 cell-derived exosomes remain largely unknown. Methods In this study, NK92 cell-derived exosomes were isolated via ultracentrifugation. Small RNA sequencing and proteomic sequencing were performed on both the cells and their exosomes. To enhance exosome targeting to tumor cells, the tLyP-1 targeting peptide was displayed on NK92 cell surfaces through genetic engineering. The mechanism underlying tumor therapy mediated by NK92 cell-derived exosomes was investigated through in vitro and in vivo experiments. Additionally, we designed a cholesterol-modified ABCB1 siRNA that adsorbs onto exosome surfaces and enters recipient cells to silence target genes. Results First, small RNA sequencing and proteomic analysis of NK92 cells and NK92 cell-derived exosomes revealed that the exosomes retained the anti-tumor activity of parental NK cells, inhibiting tumor progression by modulating apoptosis, proliferation, and metastasis. Second, tLyP-1-modified exosomes exhibited enhanced tumor-targeting specificity and exerted anti-tumor effects via the miR-31-5p- GPRC5A a...