HS-Activatable Nanoagent for NIR-II Fluorescence Imaging and Photodynamic Therapy of Colon Cancer.

Colon cancer poses a serious health threat due to its asymptomatic early progression, recurrence rate, and the limited efficacy of current diagnostic and therapeutic strategies, highlighting the urgent need for noninvasive and effective theranostic methods. Photosensitizers capable of integrating NIR-II fluorescence imaging with photodynamic therapy (PDT) in a single platform offer a promising solution but often suffer from inadequate specificity, leading to off-target effects and reduced theranostic accuracy. In this study, we exploit the elevated HS levels in the colonic tumor microenvironment to develop a HS-activatable NIR-II phototheranostic nanoplatform for the precise diagnosis and treatment of colon cancer. This nanoplatform is based on an optimized NIR-II fluorescent photosensitizer that is caged with HS-cleavable 2,4-dinitrophenyl groups and then is coassembled with amphiphilic polymers to form the water-dispersible nanoparticles (BIS-NPs). Upon exposure to HS, BIS-NPs exhibit selective activation of NIR-II fluorescence and singlet oxygen (O) generation under 808 nm laser irradiation. Systematic evaluation in CT26 tumor-bearing mice demonstrates that BIS-NPs enable tumor-specific NIR-II fluorescence imaging and efficient PDT performance, confirming their potential as a precise and effective phototheranostic tool for colon cancer management.