Abstract：
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.
摘要：
O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）是胶质母细胞瘤（GBM）患者替莫唑胺（TMZ）敏感性的关键决定因素。小干扰RNA（siRNA）靶向MGMT以增强TMZ敏感性的治疗潜力受到血清核酸酶降解的阻碍，脱靶效应,在肿瘤部位积累不良，和低血液循环。在这项研究中,我们开发了基于核酸的框架纳米颗粒(FNN)，它由六螺旋DNA束构成，封装和保护siMGMT，以提高GBM治疗中的TMZ敏感性。为了更好的血脑屏障（BBB）渗透和GBM靶向，我们将血管肽-2(ANG)靶向模块缀合到FNN的每一端。核仁素（NCL）响应锁是沿着六螺旋DNA束的侧面设计的，在肿瘤进入前保护siMGMT。在与肿瘤过表达的NCL相互作用时，这些锁解锁,暴露siMGMT,这可以有效抑制MGMT，导致GBM中TMZ治疗功效的显着改善。这种创新策略有可能改变GBM的当前治疗环境。
