Department of Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Department of Neurosurgery, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Drug Resist Updat. 2024 Sep;76:101122. doi: 10.1016/j.drup.2024.101122. Epub 2024 Jul 27.
O-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.
O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）是胶质母细胞瘤（GBM）患者对替莫唑胺（TMZ）敏感性的重要决定因素。针对 MGMT 的小干扰 RNA（siRNA）靶向治疗增强 TMZ 敏感性的治疗潜力受到血清核酸酶降解、脱靶效应、在肿瘤部位的蓄积不良以及在血流中的循环低等因素的阻碍。在这项研究中，我们开发了一种基于框架核酸的纳米颗粒（FNN），它由六螺旋 DNA 束构建而成，用于包裹和保护 siMGMT，以提高 GBM 治疗中 TMZ 的敏感性。为了更好地穿透血脑屏障（BBB）和靶向 GBM，我们在 FNN 的每端连接了靶向血管生成素-2（ANG）的模块。在六螺旋 DNA 束的两侧设计了核仁素（NCL）响应锁，在肿瘤进入之前保护 siMGMT。与肿瘤过表达的 NCL 相互作用后，这些锁会解锁，暴露出 siMGMT，从而有效抑制 MGMT，显著提高 TMZ 在 GBM 中的治疗效果。这种创新策略有可能改变 GBM 的当前治疗格局。
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