mTOR-siRNA-conjugated and Gboxin-loaded micelles for mitochondrial dysfunction-driven synergistic glioblastoma therapy

Targeting mitochondrial-mediated energy metabolism has emerged as a promising therapeutic strategy for glioblastoma multiforme (GBM), given its crucial role in sustaining the rapid growth and survival of tumor cells. In this study, we developed a combinatorial, non-cationic siRNA-conjugated self-assembled micelle system core-encapsulated with Gboxin (siRNA-micelle@Gboxin) designed to induce severe mitochondrial dysfunction in GBM cells. The mTOR-siRNA component in the micelle silences mTOR expression, downregulates mTORC1 activity, and reduces 4EBP1 phosphorylation, leading to inhibition of mRNA translation and disruption of cellular energy metabolism, ultimately resulting in decreased ATP production. Concurrently, the GBM-specific drug Gboxin inhibits oxidative phosphorylation (OXPHOS), directly inducing mitochondrial dysfunction and exacerbating the energy crisis within glioma cells, synergistically accelerating apoptosis through mitochondrial damage. Notably, this dual-target inhibition of mTORC1 and OXPHOS by siRNA-micelle@Gboxin resulted in a more potent, synergistic anti-tumor effect than targeting either pathway alone. These findings highlight that the Gboxin-loaded siRNA micelle offers a promising and innovative nanotherapeutic approach for GBM treatment, harnessing the synergistic effects of gene silencing and chemotherapy-based mitochondrial disruption to achieve a powerful therapeutic efficacy.