Copper/tetrasulfide co-doped mesoporous organosilica for multimodal imaging-guided photothermal tumor stiffness modulation and synergistic chemo-chemodynamic therapy of triple-negative breast cancer.

Elevated tumor stiffness, mainly caused by dense extracellular matrix deposition, severely restricts nanodrug penetration and weakens the efficacy of combined cancer therapy for triple-negative breast cancer. Herein, we developed a copper/tetrasulfide co-doped mesoporous organosilica (CM) coated with polydopamine and loaded with doxorubicin, termed DCMP, to integrate chemotherapy, chemodynamic therapy, photothermal therapy, and tumor stiffness modulation. The copper/tetrasulfide co-doped framework endowed the carrier with tumor microenvironment-responsive degradability, Cu-mediated glutathione depletion, and Fenton-like catalytic activity, while the polydopamine coating enabled near-infrared (NIR)-responsive photothermal conversion and controlled drug release. DCMP exhibited a high drug loading capacity of 47.08% and a photothermal conversion efficiency of 28%. Under acidic, reductive, and NIR-stimulated conditions, DCMP promoted DOX release and enhanced oxidative stress through GSH depletion and ·OH generation. In 4T1 cells, DCMP combined with NIR irradiation showed potent synergistic cytotoxicity. In vivo fluorescence and photoacoustic imaging confirmed effective tumor accumulation at 8 h post-injection. Upon 808 nm laser irradiation, DCMP rapidly increased the tumor temperature to 49.6 °C and achieved a tumor inhibition rate of 88.05%. Histological and immunofluorescence analyses further revealed that DCMP + NIR induced extensive tumor apoptosis, reduced Ki67 expression, upregulated Bax and caspase-3, downregulated Bcl-2, and an increased Bax/Bcl-2 ratio. Moreover, shear wave elastography and matrix staining demonstrated that photothermal treatment reduced tumor stiffness and remodeled extracellular matrix components, including collagen, α-SMA, collagen I, and fibronectin, thereby facilitating deeper drug penetration. Overall, DCMP provides a multimodal imaging-guided nanotherapeutic strategy that combines chemical tumor killing with physical tumor matrix modulation to enhance chemo-chemodynamic-photothermal antitumor therapy.