Department of Radiotherapy and Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan 475004, China; Henan-Macquarie Uni Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, Henan International Joint Laboratory of Nanobiomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China.
Henan-Macquarie Uni Joint Centre for Biomedical Innovation, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, Henan International Joint Laboratory of Nanobiomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China.
J Control Release. 2024 Dec;376:67-78. doi: 10.1016/j.jconrel.2024.10.004. Epub 2024 Oct 9.
Glioblastoma multiforme (GBM), the most aggressive intracranial neoplasm, remains incurable at present, primarily due to drug resistance, which significantly contributes to elevated recurrence rates and dismal prognosis. Signal transducer and activator of transcription 3 (STAT3) is a critical gene closely associated with GBM drug resistance and the progression of GBM stem cells (GSCs), making it a promising therapeutic target. In this study, we developed cancer cell membrane-cloaked biomimetic nanoparticles to deliver STAT3 siRNA to reverse drug resistance in homologous GBM. These biomimetic nanoparticles leverage homotypic targeting, rapid endosome escape, and fast siRNA release, leading to efficient in vitro STAT3 knockdown in both temozolomide-resistant U251-TR cells and X01 GSCs. Moreover, benefited from the membrane functionalization, significant prolonged blood circulation, improved blood brain barrier (BBB) penetration and GBM tumor accumulation are achieved by these siRNA biomimetic nanoparticles. Importantly, these nanoparticles effectively inhibit tumor proliferation, significantly extending median survival time in orthotopic U251-TR (43.5 d versus 20 d for PBS control) and X01 GSC-bearing mouse xenografts (52 d versus 19.5 d for PBS control). Altogether, this biomimetic siRNA platform offers a promising strategy for gene therapy targeting drug-resistant GBM.
胶质母细胞瘤（GBM）是目前最具侵袭性的颅内肿瘤，仍然无法治愈，主要是由于耐药性，这显著导致了复发率升高和预后不良。信号转导子和转录激活子 3（STAT3）是与 GBM 耐药性和 GBM 干细胞（GSCs）进展密切相关的关键基因，使其成为有前途的治疗靶点。在这项研究中，我们开发了癌细胞膜伪装仿生纳米颗粒，将 STAT3 siRNA 递送至同源 GBM 以逆转耐药性。这些仿生纳米颗粒利用同型靶向、快速内体逃逸和快速 siRNA 释放，在替莫唑胺耐药的 U251-TR 细胞和 X01 GSCs 中均实现了有效的体外 STAT3 敲低。此外，得益于膜功能化，这些 siRNA 仿生纳米颗粒显著延长了血液循环时间，提高了血脑屏障（BBB）通透性和 GBM 肿瘤积累。重要的是，这些纳米颗粒有效地抑制了肿瘤的增殖，显著延长了荷瘤小鼠的中位生存时间，在原位 U251-TR（PBS 对照组为 20 天，纳米颗粒组为 43.5 天）和 X01 GSC 荷瘤小鼠（PBS 对照组为 19.5 天，纳米颗粒组为 52 天）中均如此。总之，这种仿生 siRNA 平台为针对耐药性 GBM 的基因治疗提供了一种有前途的策略。
