Preventing Glioblastoma Relapse by Igniting Innate Immunity through Mitochondrial Stress in the Surgical Cavity

作者：Xu Han, Fan Feng, Zixu Wang, Shujun Huang, Kaiyan Xi, Z Fang, Jianyu Shen, Mingrui Wang, Yi Zhang, Yi Zhang, Ben Liu, Junpeng Wang, Jiahao Wang, Xiangjun Liang, Guangpan Sun, Runlu Zhang, Baoteng Han, Fanlin Liu, Mingze Li, Xun Zhang, Jingjing Wang, Huimin Geng, Yanrong Zhang, Yanrong Zhang, Wenli Zhang, Zimei Wu, Xingang Li, Yi Li, Lijun Cheng, Yulin Zhang, Yulin Zhang, Shilei Ni · 发表于：Advanced Materials · 年份：2025 · DOI：10.1002/adma.202511351 · 被引用次数：2 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer、Extracellular vesicles in disease

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.