Injectable intelligent hydrogel harnessing sulfur-vacancy bimetallic sulfides for multimodal synergistic cancer...

The unique characteristics of the tumor microenvironment, such as its acidity and redox imbalance, provide opportunities for designing smart, stimuli-responsive therapeutic systems. In this study, a novel injectable hydrogel system consisting of bimetallic sulfides (CoS_x@CuS_y), the chemotherapeutic agent doxorubicin (DOX), and sodium alginate (SA) was developed and named DSH. Upon activation by near-infrared (NIR) laser irradiation, the sulfur-vacancy-enriched CoS_x@CuS_y exhibited superior photothermal conversion efficiency (30.5 %) and effectively generated singlet oxygen (¹O₂), facilitating synergistic photothermal therapy (PTT) and photodynamic therapy (PDT). Additionally, ultrasound stimulation induced ¹O₂ production from CoS_x@CuS_y, thereby eliciting a sonodynamic therapeutic effect. The copper ions (Cu²⁺) released from CoS_x@CuS_y accumulated in tumor cells, triggering cuproptosis, whereas the released S^2- ions underwent conversion to hydrogen sulfide in the mildly acidic tumor microenvironment. To enhance antitumor performance, the hydrogel facilitated precisely controlled release of DOX in the tumor microenvironment. In vivo experiments demonstrated that the combination of the DSH hydrogel with NIR and ultrasound irradiation significantly inhibited tumor growth, achieving a tumor inhibition rate as high as 96.1 %. These results highlight the remarkable therapeutic potential of DSH in synergistic multimodal treatment.