Wang Bin, Tang Maoping, Yuan Ziwei, Li Zhongyu, Hu Bin, Bai Xin, Chu Jinxian, Xu Xiaoyang, Zhang Xue-Qing
Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, PR China.
Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, 07102, USA.
Bioact Mater. 2022 Mar 1;16:232-248. doi: 10.1016/j.bioactmat.2022.02.026. eCollection 2022 Oct.
Immunotherapy is emerging as a powerful tool for combating many human diseases. However, the application of this life-saving treatment in serious brain diseases, including glioma, is greatly restricted. The major obstacle is the lack of effective technologies for transporting therapeutic agents across the blood-brain barrier (BBB) and achieving targeted delivery to specific cells once across the BBB. Ferritin, an iron storage protein, traverses the BBB via receptor-mediated transcytosis by binding to transferrin receptor 1 (TfR1) overexpressed on BBB endothelial cells. Here, we developed bioengineered ferritin nanoparticles as drug delivery carriers that enable the targeted delivery of a small-molecule immunomodulator to achieve enhanced immunotherapeutic efficacy in an orthotopic glioma-bearing mouse model. We fused different glioma-targeting moieties on self-assembled ferritin nanoparticles via genetic engineering, and RGE fusion protein nanoparticles (RGE-HFn NPs) were identified as the best candidate. Furthermore, RGE-HFn NPs encapsulating a stimulator of interferon genes (STING) agonist (SR717@RGE-HFn NPs) maintained stable self-assembled structure and targeting properties even after traversing the BBB. In the glioma-bearing mouse model, SR717@RGE-HFn NPs elicited a potent local innate immune response in the tumor microenvironment, resulting in significant tumor growth inhibition and prolonged survival. Overall, this biomimetic brain delivery platform offers new opportunities to overcome the BBB and provides a promising approach for brain drug delivery and immunotherapy in patients with glioma.
免疫疗法正逐渐成为对抗多种人类疾病的有力工具。然而，这种挽救生命的疗法在包括胶质瘤在内的严重脑部疾病中的应用受到极大限制。主要障碍是缺乏有效的技术来将治疗药物转运穿过血脑屏障（BBB），并且一旦穿过血脑屏障后能够实现对特定细胞的靶向递送。铁蛋白是一种铁储存蛋白，通过与血脑屏障内皮细胞上过度表达的转铁蛋白受体1（TfR1）结合，经受体介导的转胞吞作用穿过血脑屏障。在此，我们开发了生物工程铁蛋白纳米颗粒作为药物递送载体，其能够将小分子免疫调节剂靶向递送至原位荷瘤小鼠模型中，以提高免疫治疗效果。我们通过基因工程在自组装铁蛋白纳米颗粒上融合了不同的胶质瘤靶向部分，RGE融合蛋白纳米颗粒（RGE-HFn NPs）被确定为最佳候选物。此外，包裹干扰素基因刺激剂（STING）激动剂的RGE-HFn NPs（SR717@RGE-HFn NPs）即使在穿过血脑屏障后仍保持稳定的自组装结构和靶向特性。在荷瘤小鼠模型中，SR717@RGE-HFn NPs在肿瘤微环境中引发了强烈的局部先天免疫反应，导致肿瘤生长显著抑制和生存期延长。总体而言，这种仿生脑递送平台为克服血脑屏障提供了新机会，并为胶质瘤患者的脑药物递送和免疫治疗提供了一种有前景的方法。
