Selective Manipulation of the Mitochondria Oxidative Stress in Different Cells Using Intelligent Mesoporous Silica Nanoparticles to Activate On‐Demand Immunotherapy for Cancer Treatment

Herein, the vitamin K₂ (VK₂)/maleimide (MA) coloaded mesoporous silica nanoparticles (MSNs), functional molecules including folic acid (FA)/triphenylphosphine (TPP)/tetrapotassium hexacyanoferrate trihydrate (THT), as well as CaCO₃ are explored to fabricate a core-shell-corona nanoparticle (VMM_FTTC) for on-demand anti-tumor immunotherapy. After application, the tumor-specific acidic environment first decomposed CaCO₃ corona, which significantly levitates the pH value of tumor tissue to convert M2 type macrophage to the antitumor M1 type. The resulting VMM_FTT would then internalize in both tumor cells and macrophages via FA-assisted endocytosis and free endocytosis, respectively. These distinct processes generate different amount of VMM_FTT in above two cells followed by 1) TPP-induced accumulation in the mitochondria, 2) THT-mediated effective capture of various signal ions to cut off signal transmission and further inhibit glutathione (GSH) generation, 3) ions catalyzed reactive oxygen species (ROS) production through Fenton reaction, 4) sustained release of VK₂ and MA to further enhance the ROS production and GSH depletion, which caused significant apoptosis of tumor cells and additional M2-to-M1 macrophage polarization via different processes of oxidative stress. Moreover, the primary tumor apoptosis further matures surrounding immature dendritic cells and activates T cells to continuously promote the antitumor immunotherapy.