Framework nucleic acid-based nanoparticles enhance temozolomide sensitivity in glioblastoma

• Published in: Drug resistance updates Vol. 76; p. 101122
• Main Authors: Lan, Yufei, Li, Xiaodie, Liu, Boyang, Lu, Jiankun, Zuo, Boming, Wang, Yue, Cao, Shuting, Fu, Xin, Yue, Qu, Luo, Xin, Zhong, Xiangyang, Dong, Yaoyuan, Wang, Zhao, Yang, Tao, Xie, Xinyun, Zeng, Tianci, Zhang, Manqing, Wang, Yuankai, Shen, Yixiong, Zuo, Huaqin, Zhao, Yan, Zhang, Chao, Guo, Hongbo
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.09.2024
• Subjects: DNA framework; DNA nanotechnology; Glioblastoma; SiRNA; Temozolomide sensitivity; DNA nanotechnology; SiRNA; Temozolomide sensitivity; DNA framework; Glioblastoma
• ISSN: 1368-7646; 1532-2084; 1532-2084
• DOI: 10.1016/j.drup.2024.101122

O6-methylguanine DNA methyltransferase (MGMT) is a crucial determinant of temozolomide (TMZ) sensitivity in patients with glioblastoma (GBM). The therapeutic potential of small interfering RNA (siRNA) targeting MGMT to enhance TMZ sensitivity has been hampered by serum nuclease degradation, off-target effects, poor accumulation at tumor sites, and low circulation in blood stream. In this study, we developed a framework nucleic acid-based nanoparticles (FNN), which is constructed from a six-helix DNA bundle, to encapsulate and protect siMGMT for improving TMZ sensitivity in GBM treatment. For better blood-brain barrier (BBB) penetration and GBM targeting, we conjugated Angiopep-2 (ANG) targeting modules to each end of the FNN. Nucleolin (NCL)-responsive locks were engineered along the sides of the six-helix DNA bundle, which safeguard siMGMT before tumor entry. Upon interaction with tumor-overexpressed NCL, these locks unlock, exposing siMGMT, this allows for effective suppression of MGMT, resulting in a significant improvement of TMZ therapeutic efficacy in GBM. This innovative strategy has the potential to transform the current treatment landscape for GBM. [Display omitted]