肿瘤细胞治疗研究
英文原题：Overcoming blood-brain barrier and chemoresistance in glioblastoma by Angiopep-2-modified NK cell-derived extracellular vesicles for targeted delivery of temozolomide.
胶质母细胞瘤（GBM）仍无法治愈，原因在于血脑屏障（BBB）限制了药物递送，以及肿瘤对一线化疗药物替莫唑胺（TMZ）存在固有性/获得性耐药。
胶质母细胞瘤（GBM）仍无法治愈，原因在于血脑屏障（BBB）限制药物递送，以及肿瘤对一线化疗药物 temozolomide（TMZ）存在内在性/获得性耐药。在此，我们开发了 Angiopep-2（Ang）修饰的NK 细胞来源细胞外囊泡（Ang-NK-EV），用于靶向递送 TMZ（Ang-NK-EV@TMZ），以解决这些瓶颈。NK-EV 通过 NK-92 细胞的冻融挤出法制备，负载 TMZ，并用 Ang 进行表面功能化，以靶向 LRP1（在 BBB 和 GBM 细胞上高表达）。表征证实 Ang-NK-EV@TMZ 呈球形形态，保留 EV 标志物（TSG101、CD9/63/81），并保留 NK 细胞来源的免疫因子（IFN-γ、GZMB）。体外，Ang 修饰增强了 GBM 细胞摄取（相较于 NK-EV 提高 2.5-3.2 倍）和 BBB 转胞吞（相较于游离 TMZ 提高 2.8-3.5 倍）。Ang-NK-EV@TMZ 通过调节 STING/mTOR/MGMT 信号（经由 IFN-γ）并诱导凋亡（cleaved caspase-3、γ-H2AX 升高）逆转 TMZ 耐药。它还触发免疫原性细胞死亡（ATP、HMGB1 增加），并将巨噬细胞极化为 M1 样表型。在原位 GBM 模型中，Ang-NK-EV@TMZ 在脑肿瘤中蓄积，抑制生长（相较于 PBS 生物发光低 7.2 倍），并延长中位生存期（42 天 vs. PBS 的 18 天）。未观察到显著的器官毒性或溶血。该平台整合了靶向化疗和免疫调节，突显了 NK-EV 用于 GBM 治疗的潜力。
Glioblastoma (GBM) remains incurable due to the blood-brain barrier (BBB) limiting drug delivery and intrinsic/acquired resistance to temozolomide (TMZ), the first-line chemotherapy. Here, we developed Angiopep-2 (Ang)-modified natural killer cell-derived extracellular vesicles (Ang-NK-EV) for targeted TMZ delivery (Ang-NK-EV@TMZ) to address these bottlenecks. NK-EV were prepared via freeze-thaw extrusion of NK-92 cells, loaded with TMZ, and surface-functionalized with Ang to target LRP1 (highly expressed at the BBB and on GBM cells). Characterization confirmed Ang-NK-EV@TMZ exhibited spherical morphology, preserved EV markers (TSG101, CD9/63/81), and retained NK cell-derived immune factors (IFN- , GZMB). In vitro, Ang modification enhanced GBM cell uptake (2.5-3.2-fold vs. NK-EV) and BBB transcytosis (2.8-3.5-fold vs. free TMZ). Ang-NK-EV@TMZ reversed TMZ resistance by modulating STING/ mTOR/ MGMT signaling (via IFN- ) and inducing apoptosis (elevated cleaved caspase-3, -H2AX). It also triggered immunogenic cell death (increased ATP, HMGB1) and polarized macrophages to M1-like phenotypes. In orthotropic GBM models, Ang-NK-EV@TMZ accumulated in brain tumors, inhibited growth (7.2-fold lower bioluminescence vs. PBS), and extended median survival (42 days vs. 18 days for PBS). No significant organ toxicity or hemolysis was observed. This platform integrates targeted chemotherapy and immune modulation, highlighting NK-EV' potential for GBM therapy.
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