Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, State Key Laboratory of Bioelectronics, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China.
The Translational Research Institute for Neurological Disorders, Department of Neurosurgery of Wannan Medical College, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, China.
Small. 2022 Oct;18(40):e2203448. doi: 10.1002/smll.202203448. Epub 2022 Aug 18.
Engineering a versatile nanocomplex integrating effective penetration of the blood-brain barrier (BBB), accurate diagnosis, and boosting therapy has always been an intractable challenge in glioblastoma multiforme (GBM). Herein, biomimetic nanocomplexes (TMPsM) for single intracellular transglutaminase 2 (TG2)-triggered self-assembly imaging and RNAi therapy for GBM are subtly developed. To prove the concept, transferrin receptor (TfR) aptamer-modified brain metastatic tumor cell membrane is prepared as the shell for dual BBB targeting capability and prolonged blood retention time. Upon targeting entering into GBM, hollow MnO is decomposed to release KKGKGQQ-tetraphenylethene (Pep-TPE) and siRNA. Owing to TG2 dependence, the non-emissive Pep-TPE would be self-aggregated to induce the emission turn-on in GBM that contain overexpressed TG2. The resulting aggregation-induced emission fluorescence imaging with a high signal-to-noise ratio can achieve the precise localization of the tumor and dynamic detection of TG2 activity, thereby allowing the GBM accurate diagnosis. Notably, the TG2 can be silenced by the released siRNA to cause cell apoptosis and increase chemotherapeutic sensitivity, ultimately realizing excellent antitumor efficacy. In vitro and in vivo results demonstrate that the as-prepared TMPsM indeed possess superior BBB penetration, precise diagnosis, and effective therapy of GBM. The proposed strategy may pioneer a new path for the theranostics of brain tumors.
工程化多功能纳米复合物，实现血脑屏障（BBB）的有效穿透、精确诊断和增强治疗，一直是多形性胶质母细胞瘤（GBM）的一个棘手挑战。在此，巧妙地开发了用于单细胞内转谷氨酰胺酶 2（TG2）触发的自组装成像和 GBM 的 RNAi 治疗的仿生纳米复合物（TMPsM）。为了验证这一概念，将转铁蛋白受体（TfR）适配体修饰的脑转移肿瘤细胞膜作为外壳，赋予其双重 BBB 靶向能力和延长的血液保留时间。在靶向进入 GBM 后，中空 MnO 分解以释放 KKGKGQQ-四苯乙烯（Pep-TPE）和 siRNA。由于 TG2 的依赖性，非发光性 Pep-TPE 将自组装以在含有过表达 TG2 的 GBM 中诱导发射开启。具有高信噪比的聚集诱导发射荧光成像可以实现肿瘤的精确定位和 TG2 活性的动态检测，从而实现 GBM 的精确诊断。值得注意的是，释放的 siRNA 可以沉默 TG2，导致细胞凋亡并增加化疗敏感性，最终实现优异的抗肿瘤疗效。体外和体内结果表明，所制备的 TMPsM 确实具有优异的 BBB 穿透性、精确的诊断和 GBM 的有效治疗效果。所提出的策略可能为脑肿瘤的治疗开辟新途径。
