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Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults. Emerging evidence endorses that gut dysbiosis contributes to GBM progression through the gut-brain axis (GBA), promoting inflammation and therapeutic resistance via abnormal short-chain fatty acid production and cytokine dysregulation. Exosomes, naturally occurring nanovesicles (30-150 nm), offer promising therapeutic potential due to their blood-brain barrier permeability, biocompatibility, and versatile cargo capacity. This review examines exosome engineering strategies for dual targeting: inhibiting alterations in gut microbiome and inducing regulated cell death mechanisms such as apoptosis and ferroptosis in GBM. We describe exosome engineering with detailed focus on cargo loading approaches (e.g., genetic modification, electroporation, and sonication), exosome surface functionalization with specific ligands (e.g., antibodies), and exosome biogenesis pathway manipulation. Engineered exosomes can deliver anti-inflammatory agents and gut microbiome modulators to restore GBA homeostasis while simultaneously transporting tumor-suppressive non-coding RNAs (e.g., miRNAs, siRNAs) and therapeutic agents to induce apoptosis by overcoming temozolomide resistance, and trigger ferroptosis-inducing components in GBM stem cells. Preclinical studies make obvious that this dual-targeting approach ought to enhance therapeutic efficacy by creating systemic immunity and eliminating tumor cells. However, clinical translation brings forth challenges, such as manufacturing, targeting specificity, and standardized quality control, and warrants further study.