Strategy of “Controllable Ions Interference” for Boosting MRI-Guided Ferroptosis Therapy of Tumors

Chemotherapy for oral squamous cell carcinoma (OSCC) is often marred by the development of multidrug resistance and systemic adverse effects. Metal ion interference therapy (MIIT) has risen as an innovative strategy to disrupt the intracellular metal ion equilibrium in tumor cells, potentially overcoming drug resistance. However, the effectiveness of cancer treatment that relies on delivering single metal ions to tumor site is often constrained. To address this, we have developed a therapeutic nanoplatform employing hollow mesoporous manganese dioxide nanoparticles (HMON) which harness the chelating properties of tannic acid to control the loading and release of Zn²⁺ and Pt²⁺, i.e., Zn@CDDP@HMON. In acidic tumor microenvironment, Zn²⁺ and Pt²⁺ ions strategically released from nanoplatform can inhibit mitochondrial respiration and activate NADPH oxidases (NOXs), respectively, increasing superoxide anion (O₂•^-) and hydrogen peroxide production (H₂O₂). The released Mn⁴⁺ consumes intracellular glutathione (GSH) to generate Mn²⁺, which reacts with H₂O₂ in a Fenton-like reaction, producing hydroxyl radicals (•OH) and inducing lipid peroxidation (LPO). The depletion of GSH also inhibits GPX4 activity, sensitizing tumor cells to ferroptosis. Furthermore, the reduced Mn²⁺ facilitates <i>T</i>₁-MRI imaging, allowing for real-time monitoring of nanoplatform distribution and accumulation in tumors.