Engineered Bacterial Outer Membrane Vesicles‐Based Doxorubicin and CD47‐siRNA Co‐Delivery Nanoplatform Overcomes Immune Resistance to Potentiate the Immunotherapy of Glioblastoma
Abstract
Abstract 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.
Article Details
Authors (20)
Haoyu You
Department of Pharmaceutics School of Pharmacy Minhang Hospital Key Laboratory of Smart Drug Delivery Ministry of Education Fudan University 826 Zhangheng Road Shanghai 201203 P. R. China
Shilin Zhang
School of Chemical Engineering, Faculty of Sciences, Engineering and Technology
Yiwen Zhang
Qinjun Chen
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
Yuxing Wu
Department of Pharmaceutics School of Pharmaceutical Sciences Fudan University Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Brain Function and Disorders MOE Frontiers Center for Brain Science Shanghai 201203 China
Zheng Zhou
Interdisciplinary Materials Research Center, School of Materials Science and Engineering
Zhenhao Zhao
Department of Pharmaceutics School of Pharmaceutical Sciences Fudan University Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Brain Function and Disorders MOE Frontiers Center for Brain Science Shanghai 201203 China
Boyu Su
Department of Pharmaceutics School of Pharmacy Minhang Hospital Key Laboratory of Smart Drug Delivery Ministry of Education Fudan University 826 Zhangheng Road Shanghai 201203 P. R. China
Xuwen Li
Yun Guo
Yun Chen
Weiyi Tang
Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Bing Liu
Hongrui Fan
Department of Pharmaceutics School of Pharmaceutical Sciences Fudan University Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Brain Function and Disorders MOE Frontiers Center for Brain Science Shanghai 201203 China
Shuo Geng
Virginia Tech, Blacksburg, Virginia, United States
Mingzhu Fang
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
Fangxin Li
Guangna Liu
Chen Jiang
Tao Sun