Targeted delivery of exosomal miR-484 reprograms tumor vasculature for chemotherapy sensitization

• Published in: Cancer letters 2022-04, Vol.530, p.45-58
• Main Authors: Zhao, Zongxia, Shuang, Ting, Gao, Yan, Lu, Fan, Zhang, Jinbao, He, Wei, Qu, Lijuan, Chen, Biliang, Hao, Qiang
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antibiotics; Antibodies; Apoptosis; Apoptosis - genetics; Cancer therapies; Carcinoma, Ovarian Epithelial - genetics; Cell culture; Cell Line; Cell Line, Tumor; Cell Proliferation - genetics; Chemoresistance; Chemotherapy; Down-Regulation - genetics; Drug Resistance, Neoplasm - genetics; Electroporation; Endothelial cells; Ethics; Exosomes; Exosomes - genetics; Experiments; Female; Gene expression; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Medical prognosis; Mice; Mice, Nude; MicroRNAs - genetics; Microscopy; Middle Aged; miR-484; miRNA; Neovascularization, Pathologic - genetics; Ovarian cancer; Ovarian Neoplasms - genetics; Polymerization; Proteins; Resistance; Signal Transduction - genetics; Tumors; Vascular endothelial growth factor; Vascular normalization; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.01.011

The vascular dysfunction of ovarian cancer (OC) contributes to the chemotherapeutic resistance. In this study, we aimed to explore whether exosome-mediated angiogenesis blocking could improve the chemotherapy sensitivity via vascular normalization. Exosomes were armed with RGD on the surface by fusing Lamp2b. Candidate miRNAs related to tumor angiogenesis was detected by qRT-PCR. RGD-modified exosomes were loaded with miRNAs via electroporation. The therapeutic effects of the exosomes on angiogenesis, vascular normalization, and chemotherapy sensitivity were systemically analyzed in the xenograft model. RGD-modified exosomes were relatively enriched in the tumor mass, both the tumor cell and the endothelial cells. Among the miRNA candidates, miR-484 was found down-regulated in both the cancer cells and the angiogenic endothelial cells. In vivo xenograft model experiment revealed that injection of RGD-modified exosomes loaded with miR-484 induced vessel normalization and in turn sensitized the cancer cells to chemotherapy induced apoptosis. Mechanistically, miR-484 simultaneously inhibited the expression of VEGF-A from the cancer cells and the corresponding receptors in the endothelial cells. Targeted delivery of miR-484 via RGD-modified exosomes improves the vascular normalization, sensitizes the cancer to chemotherapy, and prolongs the survival time of tumor-bearing mice after chemotherapy, opening an avenue for the clinical management of chemotherapy resistance. •Exosomes are engineered to target the vessels of tumor by surface functionalization with RGD peptide.•miR-484, an endogenous angiogenesis inhibitor, which is down-regulated in ovarian cancer cell lines and tissues, is then encapsulated into the engineered exosomes.•Targeted delivery of miR-484 improves the vascular normalization and sensitizes the cancer to chemotherapy via simultaneously targeting multiple targets in cancer cells and the endothelial cells.