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

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.