Department of Thoracic Surgery, West China Hospital of Medicine, Sichuan University, Chengdu 610044, China.
Institute of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Biomacromolecules. 2023 May 8;24(5):2063-2074. doi: 10.1021/acs.biomac.2c01493. Epub 2023 Apr 3.
Overcoming cisplatin-based drug resistance in lung cancer remains an enormous challenge in clinical tumor therapy worldwide. Recent studies have reported that some Rab GTPases are involved in multiple aspects of tumor progression, including invasion, migration, metabolism, autophagy, exosome secretion, and drug resistance. In particular, Rab26 is essential to vital processes such as vesicle-mediated secretion, cell growth, apoptosis, and autophagy. In this study, we developed a nanosystem based on programmed DNA self-assembly of Rab26 siRNA-loaded nanoparticles (siRNP). We demonstrated that siRNP could be effectively transfected into cisplatin-resistant A549 (A549/DDP) cells. These siRab26-carrying nanoparticles induced apoptosis and inhibited the disruption of autophagy. The combination therapy of siRab26 knockdown with cisplatin could improve the antitumor therapy compared with a single one in vitro. In nude mice, siRNP enhanced the chemosensitivity of cisplatin-resistant cells and inhibited tumor xenograft development. These outcomes suggest that siRNP is an effective platform for lung cancer therapy in cases exhibiting drug resistance.
克服肺癌中基于顺铂的药物耐药性仍然是全球临床肿瘤治疗中的一个巨大挑战。最近的研究报告称，一些 Rab GTPases 参与肿瘤进展的多个方面，包括侵袭、迁移、代谢、自噬、外泌体分泌和耐药性。特别是 Rab26 对囊泡介导的分泌、细胞生长、凋亡和自噬等重要过程是必不可少的。在本研究中，我们开发了一种基于 Rab26 siRNA 负载纳米颗粒（siRNP）的程序性 DNA 自组装纳米系统。我们证明了 siRNP 可以有效地转染到顺铂耐药的 A549（A549/DDP）细胞中。这些携带 siRab26 的纳米颗粒诱导细胞凋亡并抑制自噬的破坏。与单独使用顺铂相比，siRab26 敲低与顺铂联合治疗可提高体外抗肿瘤治疗效果。在裸鼠中，siRNP 增强了顺铂耐药细胞的化疗敏感性并抑制了肿瘤异种移植的发展。这些结果表明，在表现出耐药性的情况下，siRNP 是治疗肺癌的有效平台。
