Photoactivatable MoS_x/γ-MnS nanocomposite as redox dyshomeostasis amplifier for polysulfide-intensive chemodynamic cancer therapy

Redox homeostasis is a key reason for reactive oxygen species (ROS) tolerance in tumors. Complex reactive species interactome is closely related to the limited effectiveness of ROS-mediated cancer therapy. Engineering redox dyshomeostasis amplifier by disturbing the interactome of ROS with reactive sulfur species (RSS) remains a great challenge. Herein, a gelatin/cRGD–modified redox dyshomeostasis amplifier based on MoS_x/γ-MnS (MMS) hollow nanoflowers polysulfide nanocomposite was constructed by a one-pot solvothermal process for an elevated intracellular ROS level through near-infrared (NIR)-II light–activated cancer-specific polysulfide-intensive chemodynamic therapy (CDT). The NIR-II light accelerated H₂S-H₂S_2–3 (typical RSS) release in acidic tumor microenvironment (TME). Density functional theory calculations divulged that overexpressed H₂O₂ in acidic TME can augment the release of H₂S–H₂S_2–3, triggered by low activation energy of the MMS, consequently depleting glutathione (GSH) level. The form and quantity of H₂S–H₂S_2–3 can be analyzed by the advanced technology of in-situ synchrotron radiation (SR) X-ray absorption near-edge structure spectrum combined with high-performance liquid chromatograph-mass spectrometer. Simultaneously, Mn^{2 +}-releasing CDT efficiency was enhanced to produce hydroxyl radicals (·OH), breaking redox homeostasis to induce ROS accumulation in the TME. Then, the ROS amplified oxidative stress damage through synchronous ferroptosis–apoptosis, potentially eradicating tumor without metastasis.