Preventing Glioblastoma Relapse by Igniting Innate Immunity through Mitochondrial Stress in the Surgical Cavity
Abstract
Abstract Innate immunity is crucial in orchestrating the brain immune response, however, glioblastoma multiforme (GBM) has evolved sophisticated mechanisms to evade innate immune surveillance, posing significant challenges for current immunotherapies. Here, a therapeutic strategy is reported that aims at reactivating innate immune responses in GBM via targeted induction of mitochondrial stress, thereby enhancing tumor immunogenicity. Specifically, innate immune‐stimulating nanoparticles (INSTNA) are developed, encapsulating positively charged iridium‐based complexes (Ir‐mito) and small interfering RNA against Methylation‐Controlled J protein (si‐MCJ) to attenuate mitochondrial respiration. This combination effectively disrupts mitochondrial function of GBM cells, particularly when combined with tumor‐treating fields. The engineered charge‐reversal INSTNA impair the mitochondrial electron transport chain (ETC), inducing oxidative phosphorylation (OXPHOS) stress and subsequent mitochondrial matrix release. Furthermore, hydrogel‐mediated delivery of INSTNA in a postoperative GBM mouse model significantly remodeled the immunosuppressive microenvironment, resulting in pronounced tumor regression. In sum, these findings highlight that targeted induction of mitochondrial stress in postoperative GBM can potentiate innate immune activation and enhance adaptive immunity, offering a promising avenue for mitigating GBM recurrence.
Article Details
Authors (29)
Xu Han
Fan Feng
Zixu Wang
Shujun Huang
Qingdao Medical College Qingdao University Qingdao 266071 China
Kaiyan Xi
Jinan Microecological Biomedicine Shandong Laboratory, Jinan Medical and Health Science and Technology Innovation Industrial Park
Zezheng Fang
Jianyu Shen
Department of Neurosurgery Qilu Hospital and Shandong Key Laboratory of Brain Health and Function Remodeling Institute of Brain and Brain‐Inspired Science Jinan Microecological Biomedicine Shandong Laboratory Cheeloo College of Medicine Shandong University 107 Wenhua Xi Road Jinan Shandong 250012 China
Mingrui Wang
State Key Laboratory of Fine Chemicals, Frontier Science Center for Smart Materials, PSU-DUT Joint Center for Energy Research, School of Chemical Engineering
Yi Zhang
Ben Liu
Key Laboratory of Green Chemistry and Technology of Ministry of Education, National and Local Joint Engineering Laboratory of Energy Plant Bio-Fuel Preparation and Utilization College of Chemistry
Junpeng Wang
School of Polymer Science and Polymer Engineering
Jiahao Wang
Xiangjun Liang
Department of Neurosurgery Qilu Hospital and Shandong Key Laboratory of Brain Health and Function Remodeling Institute of Brain and Brain‐Inspired Science Jinan Microecological Biomedicine Shandong Laboratory Cheeloo College of Medicine Shandong University 107 Wenhua Xi Road Jinan Shandong 250012 China
Guangpan Sun
Department of Neurosurgery Qilu Hospital and Shandong Key Laboratory of Brain Health and Function Remodeling Institute of Brain and Brain‐Inspired Science Jinan Microecological Biomedicine Shandong Laboratory Cheeloo College of Medicine Shandong University 107 Wenhua Xi Road Jinan Shandong 250012 China
Runlu Zhang
Department of Neurosurgery Qilu Hospital and Shandong Key Laboratory of Brain Health and Function Remodeling Institute of Brain and Brain‐Inspired Science Jinan Microecological Biomedicine Shandong Laboratory Cheeloo College of Medicine Shandong University 107 Wenhua Xi Road Jinan Shandong 250012 China
Baoteng Han
Department of Neurosurgery Qilu Hospital and Shandong Key Laboratory of Brain Health and Function Remodeling Institute of Brain and Brain‐Inspired Science Jinan Microecological Biomedicine Shandong Laboratory Cheeloo College of Medicine Shandong University 107 Wenhua Xi Road Jinan Shandong 250012 China
Fanlin Liu
Department of Neurosurgery Qilu Hospital and Shandong Key Laboratory of Brain Health and Function Remodeling Institute of Brain and Brain‐Inspired Science Jinan Microecological Biomedicine Shandong Laboratory Cheeloo College of Medicine Shandong University 107 Wenhua Xi Road Jinan Shandong 250012 China
Mingze Li
Xun Zhang
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Jingjing Wang
Huimin Geng
Yanrong Zhang
Wenli Zhang
State Key Laboratory for Crop Genetics and Germplasm Enhancement and Utilization, CIC-MCP
Zimei Wu
Xingang Li
State Key Laboratory of Chemical Engineering and Low-Carbon Technology, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Applied Catalysis Science and Engineering, School of Chemical Engineering & Technology
Yi Li
Lian Cheng
Department of Neurosurgery Qilu Hospital and Shandong Key Laboratory of Brain Health and Function Remodeling Institute of Brain and Brain‐Inspired Science Jinan Microecological Biomedicine Shandong Laboratory Cheeloo College of Medicine Shandong University 107 Wenhua Xi Road Jinan Shandong 250012 China
Yulin Zhang
Shilei Ni