School of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, P. R. China.
Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang Province 325011, P. R. China.
ACS Appl Mater Interfaces. 2020 Jul 22;12(29):32360-32371. doi: 10.1021/acsami.0c07353. Epub 2020 Jul 10.
siRNA therapeutics as an emerging class of drug development is successfully coming to clinical utilization. The RNA-based therapy is widely utilized to explore the mechanism and cure a variety of gene-specific diseases. Tumor is an oncogene-driven disease; many genes are related to tumor progression and chemoresistance. Although human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody therapy has dramatically improved the survival rate, chemotherapy remains essential to HER2-positive (HER2+) breast cancer patients. Recently, X-box binding protein 1 (XBP1) has been involved in triple-negative breast cancer (TNBC) chemoresistance and progression, but its function in HER2+ breast cancer is poorly explored. Here, we silenced XBP1 expression using RNase-resistant RNA nanoparticles (NPs). Intravenous injection of RNA NPs with HER2-specific aptamers resulted in strong binding to tumors but not to healthy tissues. XBP1 deletion by RNA NPs impaired angiogenesis and inhibited cell proliferation, significantly suppressed breast cancer growth, and promoted the sensitization of chemotherapy in an HER2+ breast cancer mouse model. Overall, these results reveal the function of XBP1 in HER2+ breast cancer development and chemoresistance and imply that targeting XBP1 by RNA NPs may offer an easy and promising strategy for a combination treatment of breast cancer in the future.
RNA 疗法被广泛用于探索机制和治疗各种基因特异性疾病。肿瘤是一种癌基因驱动的疾病；许多基因与肿瘤进展和化疗耐药有关。虽然人表皮生长因子受体 2（HER2）靶向单克隆抗体治疗显著提高了生存率，但化疗对 HER2 阳性（HER2+）乳腺癌患者仍然至关重要。最近，X 盒结合蛋白 1（XBP1）已参与三阴性乳腺癌（TNBC）的化疗耐药和进展，但它在 HER2+乳腺癌中的功能尚未得到充分探索。在这里，我们使用 RNA 纳米颗粒（NPs）沉默了 XBP1 的表达。携带 HER2 特异性适体的 RNA NPs 的静脉注射导致与肿瘤强烈结合，但与健康组织不结合。RNA NPs 介导的 XBP1 缺失破坏了血管生成并抑制了细胞增殖，显著抑制了乳腺癌的生长，并在 HER2+乳腺癌小鼠模型中促进了化疗的敏感性。总的来说，这些结果揭示了 XBP1 在 HER2+乳腺癌发展和化疗耐药中的作用，并暗示通过 RNA NPs 靶向 XBP1 可能为未来乳腺癌的联合治疗提供一种简单而有前途的策略。
