H2S-responsive CuSe nanoparticles convert into CuSSe in situ with band gap modulation for oxygen self-supply and enhanced colon cancer phototherapy

Abstract Colorectal cancer (CRC) remains a significant challenge due to its aggressive nature and propensity for metastasis. This study presents a novel approach to CRC treatment by improved photothermal/photocatalytic/chemodynamic combination therapy in conjunction with modulation of the cancer microenvironment by scavenging endogenous hydrogen sulfide (H2S), a gasotransmitter overproduced in CRC cells. Copper selenide nanoparticles (CuSe NPs) scavenge H2S by sulfidation into copper sulfur selenium (CuSSe) NPs, leading to the in situ band gap modulation from 0.81 eV to 1.03 eV and formation of copper vacancies. These vacancies promote photothermal performances, while the change of band gap enables oxygen production via the oxidation of hydrogen peroxide at the valence band and superoxide radicals (O2•−) generation at the conduction band. Profound cytotoxic effect attained by the treatment of murine CT26 colon cancer cells with CuSe NPs and NIR-II laser irradiation corroborates the efficacy of the combined therapy alongside H2S depletion and disturbance of oxidative stress balance. Selective H2S depletion and formation of CuSSe NPs in H2S-rich colon cancer microenvironment efficiently promote the efficacy of the multimodality treatment and eradicate colon cancer in subcutaneous tumor-bearing mice. This strategy highlights the potential of in situ self-engineering nanotherapeutics with tumor microenvironmental remodeling for CRC therapy. Graphical Abstract CuSe nanoparticles are developed as an in vivo self-transforming nanotherapeutics for cancer therapy. Upon reacting with overexpressed H2S in colon cancer, these nanoparticles are converted into CuSSe with modulated band gap and copper vacancies. The transformation enhances photothermal performance, oxygen production, and photocatalytic ROS generation with H2S depletion that remodels tumor microenvironment.