Abstract

Mg-mediated immunotherapy is difficult to be activated because Mg-based nanoparticles are easily retained in tumor cells, which fails to effectively promote the infiltration of CD8+ T cells. To overcome this issue, we developed manganese peroxide nanoparticles (MP) and withaferin A (WA) loaded hollow mesoporous organosilica nanoplatform (HMON) with hyaluronic acid (HA) coating (MP@WA@HMON@HA) to activate Mg-mediated CD8+ T cell immune response. MP@WA@HMON@HA can be degraded owing to the acidity and high GSH in tumor microenvironment (TME), releasing H₂S, H₂O₂, Mg2+ and WA. The released H₂S can induce mitochondrial dysfunction and promote the generation of superoxide radicals, which reduces Fe3+ to Fe2+ to accelerate Fenton reaction generating hydroxyl radicals. WA can enhance the accumulation of toxic reactive oxygen species (ROS) by inhibiting glutathione peroxidase 4 (GPX4) activity and upregulating heme oxygenase-1 (HO-1) activity. These processes collectively promote the occurrence of gas-synergistic ferroptosis of tumor cells with ruptured tumor cell membranes, which facilitates Mg2+ release and activates Mg-mediated immune response to achieve highly efficient therapy of tumors. The experimental findings in vitro and in vivo reveal that MP@WA@HMON@HA exhibits effective inhibition of tumor growth and development, and favorable biosafety.

文章链接：https://doi.org/10.1016/j.cej.2026.174159