Magnetic traction and molecular lock-key: Nano-intelligent nanobot overcomes glioblastoma ferroptosis resistance to activate ferroptosis-immune

RNA interference (RNAi) technology, which silences disease-causing genes, offers a novel therapeutic approach for glioblastoma (GBM). However, the clinical translation of small interfering RNA (siRNA) faces challenges such as low delivery efficiency, rapid renal clearance, and endosomal/lysosomal entrapment. This study developed a dual-targeted nanoplatform FZMT, enable precise siRNA delivery while synergistically inducing ferroptosis and antitumor immunity. Under magnetic guidance, FZMT traverses the blood-brain barrier (BBB) and accumulates in tumors via TPP-mediated active targeting. Within the acidic tumor microenvironment, Fe 3 O 4 releases Fe ions that trigger Fenton reactions, depleting glutathione (GSH) and inducing lipid peroxidation (LPO). Concurrently, ZIF-8 degradation releases siMDM2 to silence MDM2, restoring p53 (TP53) function to suppress the SLC7A11-GPX4 axis and amplify ferroptosis. Furthermore, Zn 2+ and siMDM2 cooperatively activate the cGAS-STING pathway, promoting type I interferon secretion. The release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) reprograms the immunosuppressive microenvironment, enhancing dendritic cell (DC) maturation and adaptive immunity. Experimental results demonstrate that FZMT significantly suppresses GBM progression through a multi-cascade mechanism involving “magnetic targeting-molecular recognition-gene silencing-ferroptosis-immune activation”. This study presents an innovative strategy to overcome siRNA delivery barriers and achieve multimodal therapy for tumors, providing a promising paradigm for GBM treatment.