Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng, Henan 475004, China.
Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Henan Key Laboratory of Brain Targeted Bio-nanomedicine, School of Life Sciences & School of Pharmacy, Henan University, Kaifeng, Henan 475004, China.
J Control Release. 2022 May;345:696-708. doi: 10.1016/j.jconrel.2022.03.036. Epub 2022 Mar 25.
Glioblastoma (GBM) is a highly fatal and recurrent brain cancer without a complete prevailing remedy. Although the synthetic nanotechnology-based approaches exhibit excellent therapeutic potential, the associated cytotoxic effects and organ clearance failure rest major obstacles from bench to clinics. Here, we explored allogeneic bone marrow mesenchymal stem cells isolated exosomes (BMSC) decorated with heme oxygenase-1 (HMOX1) specific short peptide (HSSP) as temozolomide (TMZ) and small interfering RNA (siRNA) nanocarrier for TMZ resistant glioblastoma therapy. The BMSC had excellent TMZ and siRNA loading ability and could traverse the blood-brain barrier (BBB) by leveraging its intrinsic brain accumulation property. Notably, with HSSP decoration, the TMZ or siRNA encapsulated BMSC exhibited excellent TMZ resistant GBM targeting ability both in vitro and in vivo due to the overexpression of HMOX1 in TMZ resistant GBM cells. Further, the HSSP decorated BMSC delivered the STAT3 targeted siRNA to the TMZ resistant glioma and restore the TMZ sensitivity, consequently achieved the synergistically drug resistant GBM treatment with TMZ. Our results showed this biomimetic nanoplatform can serve as a flexible, robust and inert system for GBM treatment, especially emphasizing the drug resistant challenge.
胶质母细胞瘤（GBM）是一种高度致命且易复发的脑癌，目前尚无完全有效的治疗方法。尽管基于合成纳米技术的方法表现出了极好的治疗潜力，但相关的细胞毒性作用和器官清除失败仍是将其从实验室推向临床的主要障碍。在这里，我们探索了用血红素加氧酶-1（HMOX1）特异性短肽（HSSP）修饰的同种异体骨髓间充质干细胞分离的外泌体（BMSC）作为替莫唑胺（TMZ）和小干扰 RNA（siRNA）纳米载体，用于治疗 TMZ 耐药性胶质母细胞瘤。BMSC 具有优异的 TMZ 和 siRNA 负载能力，并可以利用其内在的脑积累特性穿透血脑屏障（BBB）。值得注意的是，通过 HSSP 修饰，TMZ 或 siRNA 包封的 BMSC 由于 TMZ 耐药性 GBM 细胞中 HMOX1 的过表达，在体外和体内均表现出优异的 TMZ 耐药性 GBM 靶向能力。此外，HSSP 修饰的 BMSC 将靶向 STAT3 的 siRNA 递送至 TMZ 耐药性神经胶质瘤，并恢复 TMZ 敏感性，从而实现与 TMZ 的协同耐药性 GBM 治疗。我们的结果表明，这种仿生纳米平台可以作为一种灵活、稳健和惰性的 GBM 治疗系统，特别是强调了耐药性挑战。
