Multifunctional glycyrrhizic acid-loaded nanoplatform combining ferroptosis induction and HMGB1 blockade for enhanced tumor immunotherapy.

Inducing ferroptotic cell death has been recognized as a promising approach in cancer therapy. However, ferroptosis can provoke tumor infiltration by myeloid-derived suppressor cells (MDSCs) through HMGB1 secretion, causing a tumor suppressive immune response. On the other hand, ferroptosis also occurs the immune cells due to its non-selective properties, which can compromise anti-tumor immunity. To address these challenges, a two-pronged approach is proposed, encompassing selectively triggered ferroptosis in tumor cells and HMGB1 blockade, aimed at eliciting systemic anti-tumor immunity and alleviating immunosuppression. Herein, GSH-specific driven nanoplatform is composed of uniform FeOOH nanospindles coated with tetrasulfide bond-bridged mesoporous organosilica (DMOS) shell, and loaded with the HMGB1 inhibitor, glycyrrhizic acid (GA). This nanoplatform is endowed with high glutathione (GSH) depletion efficiency and exhibits highly efficient Fe²⁺ and ROS generation capacity, which promotes the accumulation of LPO and subsequently induces ferroptosis. Concurrently, the inhibition of HMGB1 release counteracts the immunosuppressive effects within the tumor microenvironment. This innovative nanoplatform effectively suppresses the growth of 4T1 tumors and notably enhancing the therapeutic outcomes of immune checkpoint blockade across experimental data. The collective findings indicate its potential as a reliable therapeutic strategy for boosting ferroptosis-mediated tumor immunity with favorable safety profiles.