You Haoyu, Zhang Shilin, Zhang Yiwen, Chen Qinjun, Wu Yuxing, Zhou Zheng, Zhao Zhenhao, Su Boyu, Li Xuwen, Guo Yun, Chen Yun, Tang Weiyi, Liu Bing, Fan Hongrui, Geng Shuo, Fang Mingzhu, Li Fangxin, Liu Guangna, Jiang Chen, Sun Tao
Key Laboratory of Smart Drug Delivery/Innovative Center for New Drug Development of Immune Inflammatory Diseases (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Department of Digestive Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
Adv Mater. 2025 Apr;37(15):e2418053. doi: 10.1002/adma.202418053. Epub 2025 Mar 4.
Apart from the blood-brain barrier (BBB), the efficacy of immunotherapy for glioblastoma (GBM) is limited by the presence of intrinsic and adaptive immune resistance, implying that co-delivery of various immunotherapeutic agents or simultaneous regulation of different cells is urgently needed. Bacterial outer membrane vesicles (OMVs) offer a unique advantage in the treatment of GBM, owing to their multifunctional properties as carriers and immune adjuvants and their ability to cross the BBB. However, traditional OMVs can lead to toxic side effects and disruption of tight junctions in the BBB. Therefore, to enhance the in vivo safety and targeting capability of OMVs, we introduced engineered OMVs to reduce toxicity and further constructed a modularly assembled nanoplatform by performing simple peptide modifications. This nanoplatform demonstrates satisfactory biosafety and is able to continuously cross the BBB and target GBM with the assistance of Angiopep-2. Subsequently, immunogenic substances on OMVs, along with carried small-interfering RNA (siRNA) and doxorubicin, can promote and enhance the reprogramming and phagocytic abilities of macrophages and microglia, respectively, and increase the immunogenicity of GBM, ultimately overcoming GBM immune resistance to enhance the efficacy of immunotherapy. This OMVs-based nanoplatform provides a new paradigm and insights into the development of immunotherapy for GBM.
除血脑屏障（BBB）外，胶质母细胞瘤（GBM）免疫疗法的疗效还受到内在和适应性免疫抵抗的限制，这意味着迫切需要联合递送各种免疫治疗剂或同时调节不同细胞。细菌外膜囊泡（OMV）在GBM治疗中具有独特优势，这得益于其作为载体和免疫佐剂的多功能特性以及穿越血脑屏障的能力。然而，传统的OMV会导致毒副作用并破坏血脑屏障中的紧密连接。因此，为了提高OMV在体内的安全性和靶向能力，我们引入了工程化OMV以降低毒性，并通过简单的肽修饰进一步构建了模块化组装的纳米平台。该纳米平台具有令人满意的生物安全性，并且能够在Angiopep-2的协助下持续穿越血脑屏障并靶向GBM。随后，OMV上的免疫原性物质与携带的小干扰RNA（siRNA）和阿霉素一起，可分别促进和增强巨噬细胞和小胶质细胞的重编程和吞噬能力，并增加GBM的免疫原性，最终克服GBM免疫抵抗以提高免疫治疗的疗效。这种基于OMV的纳米平台为GBM免疫治疗的发展提供了新的范例和见解。
